Willem Overwijk, Patrick Hwu, and colleagues demonstrated that Montanide (incomplete Freund's adjuvant), which is used in a number of cancer vaccines, can induce specific T cell sequestration, dysfunction, and deletion at vaccination sites. (DOI: 10.1038/nm.3105)

An anti-PD-1 antibody developed by Bristol-Myers Squibb generates excitement with results from a phase I trial showing that, among 236 patients with various types of cancer, the treatment shrank tumors in 28 percent of melanoma patients, 30 percent of patients with kidney cancer, and 18 percent of patients with advanced non-small cell lung cancer.

Douglas J. Schwartzentruber and colleagues at The University of Texas MD Anderson Cancer Center demonstrate that patients with metastatic melanoma receiving high doses of interleukin-2 (IL-2) plus a gp100 peptide vaccine had significant improvement in overall clinical response, providing further validation for vaccine approaches to cancer treatment.

Schwartzentruber DJ, Lawson DH, Richards JM, Conry RM, Miller DM, Treisman J, Gailani F, Riley L, Conlon K, Pockaj B, Kendra KL, White RL, Gonzalez R, Kuzel TM, Curti B, Leming PD, Whitman ED, Balkissoon J, Reintgen DS, Kaufman H, Marincola FM, Merino MJ, Rosenberg SA, Choyke P, Vena D, Hwu P. gp100 peptide vaccine and interleukin-2 in patients with advanced melanoma. N Engl J Med 2011 Jun 2; 364: 2119-2127. (PMID: 21631324)

Using a novel technique to genetically modify T cells for adoptive transfer, Carl June, Michael Kalos, David Porter, Bruce Levine, and colleagues at the University of Pennsylvania School of Medicine achieve clinical responses in patients with chronic lymphocytic leukemia, including two complete, durable (one year) clinical responses, accompanied by in vivo expansion and long-term functional persistence of gene-modified cells.

Kalos M, Levine BL, Porter DL, Katz S, Grupp SA, Bagg A, June CH. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci Transl Med 2011 Aug 10; 3: 95ra73. (PMID: 21832238)

Porter DL, Levine BL, Kalos M, Bagg A, June CH. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med 2011 Aug 25; 365: 725-33. Epub 2011 Aug 10. (PMID: 21830940)

 

Steven A. Rosenberg  and colleagues at the Surgery Branch of the National Cancer Institute demonstrate that adoptive immunotherapy with CD8+ T cells genetically engineering to recognize the NY-ESO-1 antigen could induce significant tumor regressions in patients with metastatic synovial sarcoma and melanoma.

Photo courtesy of rockcellarmagazine.com

The first clear-cut benefit of Herceptin conjugated with an antimicrotubule agent is seen in patients with ‘naked’ Herceptin-resistant breast tumors.

Krop IE, Beeram M, Modi S, Jones SF, Holden SN, Yu W, Girish S, Tibbitts J, Yi JH, Sliwkowski MX, Jacobson F, Lutzker SG, Burris HA. Phase I study of trastuzumab-DM1, an HER2 antibody-drug conjugate, given every 3 weeks to patients with HER2-positive metastatic breast cancer. J Clin Oncol 2010 Jun 1; 28: 2698-2704. (PMID: 20421541)

A PD-1-specific monocolonal antibody induces frequent tumor regressions in patients with advanced melanoma, renal cancer, lung cancer, and colon cancer with very low rates of toxicity. Response correlates with tumor membrane expression of B7-H129.

Brahmer JR, Drake CG, Wollner I, Powderly JD, Picus J, Sharfman WH, Stankevich E, Pons A, Salay TM, McMiller TL, Gilson MM, Wang C, Selby M, Taube JM, Anders R, Chen L, Korman AJ, Pardoll DM, Lowy I, Topalian SL. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol 2010 Jul 1; 28: 3167-3175. (PMID: 20516446)

A CTLA-4-specific monoclonal antibody, ipilimumab (Yervoy®), is the first agent in history to provide a survival advantage in patients with advanced melanoma in a large randomized phase III trial.

Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJ, Lutzky J, Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbé C, Peschel C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A, Urba WJ. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010 Aug 19; 363: 711-723. (PMID:20525992)

Alvaro Morales reports the results of a multicenter study on the efficacy of a mycobacterial cell wall-DNA complex in patients with non-muscle invasive bladder cancer refractory to standard intravesical therapies.

Morales A, Phadke K, Steinhoff G. Intravesical mycobacterial cell wall-DNA complex in the treatment of carcinoma in situ of the bladder after standard intravesical therapy has failed. J Urol 2009 Mar; 181:1040-1044. (PMID: 19150551)

Hong Ming Shen, Ursula Storb, and colleagues show that nucleosomes inhibit access of the cytidine deaminase AID to DNA, unless the DNA is transcribed.
 

Shen HM, Poirier MG, Allen M, North J, Lal R, Widom J, Storb U. The activation induced cytidine deaminase (AID) efficiently targets DNA in nucleosomes, but only during transcription. J Exp Med 2009; 206: 1057-1071. (PMID: 19380635)

CVC researchers Danila Valmori and Maha Ayyoub identify a new NY-ESO-1 epitope, 119-143 (core region 123-137), presented by HLA-DR52b (HLA-DRB3*0202), an MHC class II allele expressed by half of Caucasians, that is immunodominant in the context of vaccine-elicited immune responses. This finding is instrumental for the immunologic monitoring of vaccination trials targeting the NY-ESO-1 tumor antigen.

Bioley G, Dousset C, Yeh A, Dupont B, Bhardwaj N, Mears G, Old LJ, Ayyoub M, Valmori D. Vaccination with recombinant NY-ESO-1 protein elicits immunodominant HLA-DR52b-restricted CD4+ T cell responses with a conserved T cell receptor repertoire. Clin Cancer Res 2009 Jul 1; 15: 4467-4474. (PMID: 19531622)

CTLA-4-specific antibodies are shown to induce tumor responses in renal and prostate cancers.
 

Small EJ, Sacks N, Nemunaitis J, Urba WJ, Dula E, Centeno AS, Nelson WG, Ando D, Howard C, Borellini F, Nguyen M, Hege K, Simons JW. Granulocyte macrophage colony-stimulating factor--secreting allogeneic cellular immunotherapy for hormone-refractory prostate cancer. Clin Cancer Res 2007 Jul 1; 13: 3883-3891. (PMID: 17606721) Download PDF

Yang JC, Hughes M, Kammula U, Royal R, Sherry RM, Topalian SL, Suri KB, Levy C, Allen T, Mavroukakis S, Lowy I, White DE, Rosenberg SA. Ipilimumab (anti-CTLA4 antibody) causes regression of metastatic renal cell cancer associated with enteritis and hypophysitis. J Immunother 2007 Nov-Dec; 30: 825-830. (PMID: 18049334 ) Download PDF

CRI Investigator Gabriel Rabinovich and his team identify a novel mechanism of T cell homeostasis based on differential glycosylation of T helper cell subsets.

Toscano MA, Bianco GA, Ilarregui JM, Croci DO, Correale J, Hernandez JD, Zwirner NW, Poirier F, Riley EM, Baum LG, Rabinovich GA. Differential glycosylation of TH1, TH2 and TH-17 effector cells selectively regulates susceptibility to cell death. Nature Immunol 2007 Aug; 8: 825-834. (PMID: 17589510)

CVC researchers, including Elke Jaeger, Julia Karbach, Danila Valmori, Maha Ayyoub, Gerd Ritter, Dirk Jaeger, Eric Hoffman, Linda Pan, Lloyd J. Old, and Alex Knuth report on the first clinical trial with virus-encoded NY-ESO-1 in a prime-boost setting.

Jäger E, Karbach J, Gnjatic S, Neumann A, Bender A, Valmori D, Ayyoub M, Ritter E, Ritter G, Jäger D, Panicali D, Hoffman E, Pan L, Oettgen H, Old LJ, Knuth A. Recombinant vaccinia/fowlpox NY-ESO-1 vaccines induce both humoral and cellular NY-ESO-1-specific immune responses in cancer patients. Proc Natl Acad Sci U.S.A 2006 Sep 26; 103: 14453-14458. (PMID: 16984998) Download PDF

Daniel Speiser, Pedro Romero, and colleauges report the first demonstration in humans that a synthetic vaccine can rapidly elicit strong specific CD8+ T cell responses in a majority of patients.
 

Speiser DE, Liénard D, Rufer N, Rubio-Godoy V, Rimoldi D, Lejeune F, Krieg AM, Cerottini JC, Romero P. Rapid and strong CD8+ T cell responses to vaccination with peptide, IFA, and CpG oligodeoxynucleotide 7909. J Clin Invest 2005 Mar; 115: 739-746. (PMID: 15696196) Download PDF

Steven A. Rosenberg and colleagues show that bulk T cells transduced with T cell receptor genes are used to treat patients with melanoma, bypassing the need to expand tumor-specific T cells from patients with cancer.
 

Morgan RA, Dudley ME, Wunderlich JR, Hughes MS, Yang JC, Sherry RM, Royal RE, Topalian SL, Kammula US, Restifo NP, Zheng Z, Nahvi A, de Vries CR, Rogers-Freezer LJ, Mavroukakis SA, Rosenberg SA. Cancer regression in patients after transfer of genetically engineered lymphocytes. Science 2006 Oct 6; 314: 126-129. (PMID: 16946036) Download PDF

Christophe Lurquin, Thierry Boon, and Pierre Coulie show that post-vaccination melanoma regression involves tumor-specific T cells, some of which being already present before vaccination, that recognize antigens different than those of the vaccine. It suggests that immunosuppression prevails in tumors prior to vaccination.
 

Germeau C, Ma W, Schiavetti F, Lurquin C, Henry E, Vigneron N, Brasseur F, Lethé B, De Plaen E, Velu T, Coulie PG. High frequency of anti-tumor T cells in the blood of melanoma patients before and after vaccination with tumor antigens. J Exp Med 2005 Jan 17; 201: 241-248. (PMID: 15657293) Download PDF

Lurquin C, Lethé B, Corbière V, Théate I, van Baren N, Coulie PG, Boon T. Contrasting frequencies of anti-tumor and anti-vaccine T cells in metastases of a melanoma patient vaccinated with a MAGE tumor antigen. J Exp Med 2005 Jan 17; 201: 249-257. (PMID: 15657294) Download PDF

Daniel E. Speiser and coworkers demonstrate that human cancer-specific cytotoxic CD8 T cells are strongly activated after vaccination with peptides and CpG oligonucleotides, representing the currently most powerful synthetic cancer vaccine formulation.[i] Consequently, circulating cancer-specific T-cells become highly functional in vivo, which correlates with disease-free survival of melanoma patients.[ii]
 

[i] Speiser DE. Lienard D, Rufer N, Rubio-Godoy V, Rimoldi D, Lejeune F, Krieg AM, Cerottini JC, Romero P. Rapid and strong human CD8+ T cell responses to vaccination with peptide, IFA, and CpG oligodeoxynucleotide 7909. J Clin Invest 2005 Mar; 115: 739-746. (PMID: 15696196) Download PDF

[ii] Baumgaertner P, Jandus C, Rivals JP, Derre L, Lovgren T, Baitsch L, Guillaume P, Luescher IF, Berthod G, Matter M, Rufer N, Michielin O, Speiser DE. Vaccination-induced functional competence of circulating human tumor-specific CD8 T-cells. Int J Cancer 2011 Jul 27. (PMID: 21796616)

Michael Dustin and Takashi Saito demonstrate TCR signaling microclusters with natural ligands and establish their relationship to supramolecular activation clusters (SMACs).

Campi G, Varma R, Dustin ML. Actin and agonist MHC-peptide complex-dependent T cell receptor microclusters as scaffolds for signaling. J Exp Med 2005 Oct 17; 202: 1031-1036. (PMID: 16216891) Download PDF

Varma R, Campi G, Yokosuka T, Saito T, Dustin ML. T cell receptor-proximal signals are sustained in peripheral microclusters and terminated in the central supramolecular activation cluster. Immunity 2006 Jul; 25: 117-127. (PMID: 16860761) Download PDF

Rong-Fu Wang and colleagues are the first to describe a mechanism that can reverse immune suppression by regulatory T cells, mediated through Toll-like receptor 8.
 

Peng G, Guo Z, Kiniwa Y, Voo KS, Peng W, Fu T, Wang DY, Li Y, Wang HY, Wang RF. Toll-like receptor 8-mediated reversal of CD4+ regulatory T cell function. Science 2005 Aug 26; 309: 1380-1384. (PMID: 16123302)

Wolf Hervé Fridman and Jérôme Galon report in the New England Journal of Medicine and Science providing quantitative insights into the immune variables involved in the clinical course and prognosis in colorectal cancer and demonstrating that the type, density, and location of immune cells within tumor samples were found to be a better predictor of patient survival than previous pathological criteria for tumor staging.
 

Pagès F, Berger A, Camus M, Sanchez-Cabo F, Costes A, Molidor R, Mlecnik B, Kirilovsky A, Nilsson M, Damotte D, Meatchi T, Bruneval P, Cugenc P-H, Trajanoski Z, Fridman W-H, Galon J. Effector memory T cells, early metastasis, and survival in colorectal cancer. N Engl J Med 2005 Dec 22; 353: 2654. (PMID: 16371631)

Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pagès C, Tosolini M, Camus M, Berger A, Wind P, Zinzingohoué, Bruneval P, Cugenc P-H, Trajanoski Z, Fridman W-H, Pagès. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 2006 Sep 29; 313: 1960-1964. (PMID: 17008531)

The first tumor antigenic peptides produced by peptide splicing are reported by Ken-Ichi Hanada and James C. Yang[i] and by Nathalie Vigneron and Benoit Van den Eynde.[ii] The latter authors further show that peptide splicing occurs in the proteasome by transpeptidation.

[i] Hanada K, Yewdell JW, Yang JC. Immune recognition of a human renal cancer antigen through post-translational protein splicing. Nature 2004 Jan 15; 427: 252-256. (PMID: 14724640)

[ii] Vigneron N, Stroobant V, Chapiro J, Ooms A, Degiovanni G, Morel S, van der Bruggen P, Boon T, Van den Eynde B. An antigenic peptide produced by peptide splicing in the proteasome. Science 2004 Apr 23; 304: 587-590. (PMID: 15001714)

Warren EH, Vigneron NJ, Gavin MA, Coulie PG, Stroobant V, Dalet A, Tykodi SS, Xuereb SM, Mito JK, Riddell SR, Van den Eynde BJ. An antigen produced by splicing of noncontiguous peptides in the reverse order. Science 2006 Sep 8; 313: 1444-1447. (PMID: 16960008)

CRI Investigator Gabriel Rabinovich and his team identify a novel strategy mediated by secretion of the sugar-binding protein galectin-1 that is used by tumors to escape the immune response.

“As a recipient of a CRI Investigator Research Award and a scientist working in South America, I have to say that receiving a grant from the CRI was the best experience at the beginning of my scientific career in Tumor Immunology.” – Gabriel Rabinovich
 

Rubinstein N, Alvarez M, Zwirner NW, Toscano MA, Ilarregui JM, Bravo A, Mordoh J, Fainboim L, Podhajcer OL, Rabinovich GA. Targeted inhibition of galectin-1 gene expression in tumor cells results in heightened T cell-mediated rejection; A potential mechanism of tumor-immune privilege. Cancer Cell 2004 Mar; 5: 241-251. (PMID: 15050916)

A Cancer Vaccine Collaborative (CVC) phase 1 clinical trial at the Weill Medical College of Cornell University successfully demonstrates that vaccination with a cancer-specific recombinant protein antigen can successfully induce a fully integrated immune response in humans, consisting of antibody, CD4+ T cell, and CD8+ T cell responses. In the trial, patients with non-small cell lung cancer were treated with a vaccine consisting of the cancer antigen MAGE-3 and GlaxoSmithKline’s immunological adjuvant AS02B. The study found that vaccine injection induced a MAGE-3 specific T cell and antibody response.


Atanackovic D, Altorki NK, Stockert E, Williamson B, Jungbluth AA, Ritter E, Santiago D, Ferrara CA, Matsuo M, Selvakumar A, Dupont B, Chen Y-T, Hoffman EW, Ritter G, Old LJ, Gnjatic S. Vaccine-induced CD4+ T cell responses to MAGE-3 protein in lung cancer patients. J Immunol 2004 Mar 1; 172: 3289-3296. (PMID: 14978137) Download PDF

Vincenzo Cerundolo and colleagues demonstrate that co-injection of invariant natural killer T (iNKT) cell agonists together with antigenic proteins enhances antigen-specific CD4 and CD8 T cell responses. This concept has been tested in the clinic to jump-start antigen-specific T and B cell responses.
 

Hermans IF, Silk JD, Gileadi U, Salio M, Mathew B, Ritter G, Schmidt R, Harris AL, Old LJ, Cerundolo V. NKT cells enhance CD4+ and CD8+ T cell responses to soluble antigen in vivo through direct interaction with dendritic cells. J Immunol 2003 Nov 15; 171: 5140-5147. (PMID: 14607913) Download PDF

Shimon Sakaguchi and colleagues report that the transcription factor Foxp3 is a key regulatory gene for the development of regulatory T cells.[i] Soon after, two papers, by Alexander Rudensky[ii] and by Roli Khattri and Fred Ramsdell,[iii] report in Nature Immunology that Foxp3 is expressed by CD4+CD25+ regulatory T cells and programs their development and function.
 

[i] Hori S, Nomura T, Sakaguchi S.Control of regulatory T cell development by the transcription factor Foxp3. Science 2003 Feb 14; 299: 1057-1061. (PMID: 12522256)

[ii] Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nature Immunol 2003 Apr; 4: 330-336. (PMID: 12612578)

[iii] Khattri R, Cox T, Yasayko SA, Ramsdell F. An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nature Immunol 2003 Apr; 4: 330-336. (PMID: 12612581)

Benoit Van den Eynde shows that tumors frequently express tryptophan-degrading enzyme indoleamine 2,3-dioxygenase (IDO) and thereby resist immune rejection. This work opens the way to the search for IDO inhibitors to boost the efficacy of cancer vaccines.

Uyttenhove C, Pilotte L, Theate I, Stroobant V, Colau D, Parmentier N, Boon T, Van den Eynde BJ. Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Nat Med 2003 Oct; 9: 1269-1274. (PMID: 14502282)

George Coukos and colleagues provide the first data indicating a relationship between tumor immunity and ovarian patient outcomes, reporting that the presence of tumor-infiltrating lymphocytes in the primary tumor strongly correlated with patient survival.

Zhang L, Conejo-Garcia JR, Katsaros D, Gimotty PA, Massobrio M, Regnani G, Makrigiannakis A, Gray H, Schlienger K, Liebman MN, Rubin SC, Coukos G. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med 2003 Jan 16; 348: 203-213. (PMID: 12529460)

A CTLA-4-specific antibody, inhibiting the CTLA-4-mediated immune checkpoint, induces clinical regressions in patients with advanced melanoma (but also causes immune-related toxicity).

DOI: 10.1073/pnas.0830997100

Two studies show for the first time that adoptive T cell therapy for patients with advanced melanoma using in vitro-expanded T cells can cause tumor regressions.
 

Yee C, Thompson JA, Byrd D, Riddell SR, Roche P, Celis E, Greenberg PG. Adoptive T cell therapy using antigen-specific CD8+ T cell clones for the treatment of patients with metastatic melanoma: in vivo persistence, migration, and antitumor effect of transferred T cells. Proc Natl Acad Sci U.S.A 2002 Dec 10; 99: 16168-16173. (PMID: 12427970) Download PDF

Dudley ME, Wunderlich JR, Robbins PF, Yang JC, Hwu P, Schwartzentruber D, Topalian SL, Sherry R, Restifo NP, Hubicki AM, Robinson MR, Raffeld M, Duray P, Seipp CA, Rogers-Freezer L, Morton KE, Mavroukakis SA, White DE, Rosenberg SA. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science 2002 Oct 25; 298: 850-854. (PMID: 12242449) Download PDF

Larry Samelson and colleagues report the description of signaling microclusters containing the TCR with critical signaling enzymes and adapter molecules.

Bunnell SC, Hong DI, Kardon JR, Yamazaki T, McGlade CJ, Barr VA, Samelson LE. T cell receptor ligation induces the formation of dynamically regulated signaling assemblies. J Cell Biol 2002 Sep 30; 158: 1263-1275. (PMID: 12356870) Download PDF

Vincenzo Cerundolo and colleagues report on studies of the structural, kinetic, and functional analysis of lipid binding to CD1 molecules. To gain insights into the structure and function of CD1 molecules, the researchers applied two novel refolding protocols and were able to solve the crystal structure of CD1b molecules with distinct lipid antigens[i] and CD1d molecules loaded with the NKT cell agonist alphaGalactosylCeramide.[ii] These structures clarified for the first time the ligand-binding mechanisms of CD1b via a network of four interlinked hydrophobic channels, which provide a unique adaptable system required to present a broad range of ligands and the ability of CD1d molecules to undergo conformational change.
 

[i] Gadola SD, Zaccai NR, Harlos K, Shepherd D, Castro-Palomino JC, Ritter G, Schmidt RR, Jones EY, Cerundolo V. Structure of human CD1b with bound ligands at 2.3 A, a maze for alkyl chains. Nat Immunol 2002 Aug; 3: 721-726. (PMID: 12118248)

[ii] Koch M, Stronge VS, Shepherd D, Gadola SD, Mathew B, Ritter G, Fersht AR, Besra GS, Schmidt RR, Jones EY, Cerundolo V. The crystal structure of human CD1d with and without alpha-galactosylceramide. Nat Immunol 2005 Aug; 6: 819-826. (PMID: 16007090)

Pramod Srivastava, Giorgio Parmiani, and colleagues report that immunization with autologous tumor-derived gp96-peptide complexes elicits tumor regression in stage IV melanoma patients, without any immunization-related adverse events.
 

Belli R, Testori A, Rivoltini L, Maio M, Andreola G, Sertoli MR, Gallino G, Piris A, Cattelan A, Lassari I, Carrabba M, Scita G, Santantonio C, Pilla L, Tragni G, Lombardo C, Arienti F, Marchianò A, Bertolini F, Cova A, Lamaj E, Ascani L, Camerini R, Corsi M, Cascinelli N, Lewis JJ, Srivastava PK, Parmiani G. Vaccination of metastatic melanoma patients with autologous Tumor-derived heat shock protein gp96-peptide complexes. J Clin Oncol 2002 Oct 15 ; 20: 4169-4180. (PMID: 12377960)
 

Researchers, including Mark J. Smyth, provide the first demonstration that TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) is critical in immune surveillance of cancer.

Takeda K, Hayakawa Y, Smyth MJ, Kayagaki N, Yamaguchi N, Kakuta S, Iwakura Y, Yagita H, Okumura K. Involvement of tumor necrosis factor-related apoptosis-inducing ligand in surveillance of tumor metastasis by liver NK cells. Nature Medicine 2001 Jan 7; 7: 94-100. (PMID: 11135622)

David Raulet and Lewis Lanier, separately, show that tumor cells expressing ligands for the natural killer cell activating receptor NKG2D are destroyed by natural killer cells in vivo, establishing a new mechanism for how natural killer cells recognize tumor cells.
 

Diefenbach A, Jensen ER, Jamieson AM, Raulet DH. Rae1 and H60 ligands of the NKG2D receptor stimulate tumour immunity. Nature 2001 Sep 13; 413: 165-171. (PMID: 11557981)

Cerwenka A, Baron JL, Lanier LL. Ectopic expression of retinoic acid early inducible-1 gene (RAE-1) permits natural killer cell-mediated rejection of a MHC class I-bearing tumor in vivo. Proc Natl Acad Sci U.S.A 2001 Sep 25; 98: 11521-11526. (PMID: 11562472) Download PDF

David Raulet and Lewis Lanier, separately, show that tumor cells expressing ligands for the natural killer cell activating receptor NKG2D are destroyed by natural killer cells in vivo, establishing a new mechanism for how natural killer cells recognize tumor cells.
 

Diefenbach A, Jensen ER, Jamieson AM, Raulet DH. Rae1 and H60 ligands of the NKG2D receptor stimulate tumour immunity. Nature 2001 Sep 13; 413: 165-171. (PMID: 11557981)

Cerwenka A, Baron JL, Lanier LL. Ectopic expression of retinoic acid early inducible-1 gene (RAE-1) permits natural killer cell-mediated rejection of a MHC class I-bearing tumor in vivo. Proc Natl Acad Sci U.S.A 2001 Sep 25; 98: 11521-11526. (PMID: 11562472) Download PDF

John M. Kirkwood and ECOG report the second independent adjuvant interferon trial to improve both relapse-free and overall survival compared to a vaccine control. (E1694)

Michael O’Donell reports on the efficacy of the combination of interferon-alpha 2b plus low dose BCG in patients with BCG refractory bladder cancer.

O’Donell MA, Krohn J, DeWolf WC. Salvage intravesical therapy with interferon-alpha 2b plus low dose bacillus Calmette-Guerin is effective in patients with superficial bladder cancer in whom bacillus Calmette-Guerin alone previously failed. J Urol 2001 Oct; 166: 1300-1305. (PMID: 11547062)

Reporting in the journal Nature, Stanley G. Nathenson and his colleague Steven C. Almo, at Albert Einstein College of Medicine,[i] and William S. Somers and colleagues at Wyeth Research in Cambridge, MA,[ii] crystallize and solve the 3D structure of the powerful negative T cell regulatory molecule CTLA-4 in complex with its ligand B-7. This revealing structure demonstrates that CTLA-4 occurrs as a dimer with bivalent properties allowing it to bind 2 B-7 dimers and form an alternating array likely important for its negative signaling capabilities. CTLA-4 has since been shown to have important therapeutic uses. Dr. Nathenson and colleagues also solved the 3D structure of the critical T cell molecules PD-1/PD-L1. Strategies to manipulate the PD-1 pathway are currently being tested in clinical trials for cancer and HIV/AIDS.
 

[i] Schwartz J-C D, Zhang X, Fedorov AA, Nathenson SG, Almo SC. Structural basis for co-stimulation by the human CTLA-4/B7-2 complex. Nature 2001 Mar 29; 410: 604-608. (PMID: 11279501)

[ii] Stamper CC, Zhang Y, Tobin JF, Erbe DV, Ikemizu S, Davis SJ, Stahl ML, Seehra J, Somers WS, Mosyak L. Crystal structure of the B7-1/CTLA-4 complex that inhibits human immune responses. Nature 2001 Mar 29; 410: 608-611. (PMID: 11279502)

Two ligands for PD-1 are identified: B7-H1 (also known as PD-L1), by Lieping Chen and Tasuko Honjo, and B7-DC (also known as PD-L2), by Drew Pardoll and Tasuko Honjo.

Tseng S-Y, Otsuji M, Gorski K, Huang X, Slansky JE, Pai SI, Shalabi A, Shin T, Pardoll DM, Tsuchiya H. B7-Dc, a new dendritic cell molecule with potent costimulatory properties for T cells. J Exp Med 2001 Apr 2; 193: 839-846. (PMID: 11283156)
 

Dietmar J. Kappes discovers a mouse with a mutation in a master regulator gene controlling T cell fate. Six years later, he identifies the gene as Th-POK, and later shows that its disregulation causes lymphoid transformation. This finding is significant in linking how cells develop with how cancers develop.
 

Keefe R, Dave V, Allman D, Wiest D, Kappes DJ. Regulation of lineage commitment distinct from positive selection. Science 1999 Nov 5; 286: 1149-1193. (PMID: 10550051)

Eiichi Nakayama and colleagues first report involvement of regulatory T cells (Tregs) in the human tumor immune response.

Onizuka S, Tawara I, Shimizu J, Sakaguchi S, Fujita T, Nakayama E. Tumor rejection by in vivo administration of anti-CD25 (interleukin-2 receptor alpha) monoclonal antibody. Cancer Res 1999 Jul 1; 59: 3128-3133. (PMID: 10397255) Download PDF

Elke Jaeger, Elizabeth Stockert, Yao-Tseng Chen, Julia Karbach, Dirk Jaeger, Gerd Ritter, Lloyd J. Old, and Alex Knuth show that NY-ESO-1-specific antibody responses depend on the presence of NY-ESO-1-positive tumor cells.

Jäger E, Stockert E, Zidianakis Z, Chen YT, Karbach J, Jäger D, Arand M, Ritter G, Old LJ, Knuth A. Humoral immune responses of cancer patients against “Cancer-Testis” antigen NY-ESO-1: correlation with clinical events. Int J Cancer 1999 Oct 22; 84: 506-510. (PMID: 10502728)

James N. Ihle and colleagues demonstrate that the Stat5 proteins, redundantly, are essential mediators of IL-2 signaling in T cells.

Moriggl R, Topham DJ, Teglund S, Sexl V, McKay C, Wang D, Hoffmeyer A, van Deursen J, Sangster MY, Bunting KD, Grosveld GC, Ihle JN. 1999. Stat5 Is required for IL-2-induced cell cycle progression of peripheral T cells. Immunity 10: 249-59

Eric S. Lander and colleagues provide the first evidence that gene-expression profiling can distinguish between cancer types. In addition to distinguishing between two types of leukaemia on the basis of expression profile differences, the method could also predict their responsiveness to chemotherapy.
 

Golub TR, Slonim DK, Tamayo P, Huard C, Gaasenbeck M, Mesirov JP, Coller H, Loh ML, Downing JR, Caligiuri MA, Bloomfield CD, Lander ES. 1999. Molecular classification of cancer: class discovery and class prediction by gene expression monitoring. Science 286: 531-7

Hsiou-Chi Liou and colleagues find that c-Rel, a lymphoid-specific member of the NF-kappaB/Rel family of transcriptional factors, is essential for B lymphocyte survival and cell cycle progression, and that it is important for inducible cytokine and cytokine receptor expression and a key regulator of early activation and proliferation in T cells.

Haruo Ohtani and colleagues at the Kitasato University School of Medicine in Japan publish a landmark study showing that the presence and location of CD8+ tumor-infiltrating lymphocytes (TILs) correlates with prognosis in colon cancers, specifically that the accumulation of CD8+ T cells within the tumor predicted improved patient survival, whereas accumulation of the same cells in the tumor periphery did not correlate with survival.


Naito Y, Saito K, Shiiba K, Ohuchi A, Saigenji K, Nagura H, Ontani H. CD8+ T cells infiltrated within cancer cell nests as a prognostic factor in human colorectal cancer. Cancer Res 1998 Aug 15; 58: 3491-3494. (PMID: 9721846) Download PDF

Bruce A. Beutler establishes the genetic basis linking toll-like receptor 4 (TLR4) to the identification of microbes.

Poltorak A, He X, Smirnova I, Liu MY, Van Huffel C, Du X, Birdwell D, Alejos E, Silva M, Galanos C, Freudenberg M, Ricciardi-Castagnoli P, Layton B, Beutler B. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 1998 Dec 11; 282: 2085-2088. (PMID: 9851930)

Hong Ming Shen, Beverly Baron, and Ursula Storb show for the first time that a non-Ig gene, the proto-oncogene BCL6, is a target for somatic hypermutation, thus implying SHM as an inducer of certain B cell leukemias.

Shen H, Peters A, Baron B, Zhu X, Storb U. Mutation of BCL-6 gene in normal B cells by the process of somatic hypermutation of Ig genes. Science 1998 Jun 12; 280: 1750-1752. (PMID: 9624052)

The laboratory of Vincenzo Cerundolo is the first group to report the use of tetrameric soluble class I/peptide complexes (tetramers) for the identification of tumor-specific cytotoxic T lymphocytes (CTLs), and subsequently shows that these novel reagents allow rapid and accurate analysis of human CTL responses.
 

Dunbar PR, Ogg GS, Chen J, Rust N, van der Bruggen P, Cerundolo V. Direct isolation, phenotyping and cloning of low-frequency antigen-specific cytotoxic T lymphocytes from peripheral blood. Curr Biol 1998 Mar 26; 8: 413-416. (PMID: 9545200)

Dunbar PR, Chen JL, Chao D, Rust N, Teisserenc H, Ogg GS, Romero P, Weynants P, Cerundolo V. Cutting edge: rapid cloning of tumor-specific CTL suitable for adoptive immunotherapy of melanoma. J Immunol 1999 Jun 15; 162: 6959-6962. (PMID: 10358133) Download PDF

In collaboration with Pedro Romero, Vincenzo Cerundolo and colleagues demonstrate that, unlike virus-specific CTLs, the highest frequency of tumor-specific CTLs can be found in tumor-infiltrated lymph nodes.[i] Extending these studies to vitiligo patients, they then demonstrate using MHC class I tetramers that vitiligo patients’ PBL (peripheral blood lymphocytes) have a high frequency of skin-homing melanocyte-specific CTLs.[ii] Importantly, these results illustrate the interphase between tumor immunity and autoimmunity, since several tumor antigenic proteins are co-expressed by normal and tumor cells.
 

[i] Romero P, Dunbar PR, Valmori D, Pittet M, Ogg GS, Rimoldi D, Chen JL, Lienard D, Cerottini JC, Cerundolo V. Ex vivo staining of metastatic lymph nodes by class I major histocompatibility complex tetramers reveals high numbers of antigen-experienced tumor-specific cytolytic T lymphocytes. J Exp Med 1998 Nov 2; 188: 1641-1650. (PMID: 9802976) Download PDF

[ii] Ogg GS, Rod Dunbar P, Romero P, Chen JL, Cerundolo V. High frequency of skin-homing melanocyte-specific cytotoxic T lymphocytes in autoimmune vitiligo. J Exp Med 1998 Sep 21; 188: 1203-1208. (PMID: 9743539) Download PDF

Abraham Kupfer describes the three-dimensional structure of supramolecular activation clusters (SMACs), the interface between an antigen presenting cell and a lymphocyte (including key molecules the T cell receptor and the major histocompatibility complex), [i] later coined the immunological synapse and further elucidated by Arash Grakoui, Michael Dustin, Paul Allen, and Andrey Shaw.[ii]
 

[i] Monks CR, Freiberg BA, Kupfer H, Sciaky N, Kupfer A. Three-dimensional segregation of supramolecular activation clusters in T cells. Nature 1998 Sep 3; 395: 82-86. (PMID: 9738502)

Dustin ML, Olszowy MW, Holdorf AD, Li J, Bromley S, Desai N, Widder P, Rosenberger F, van der Merwe PA, Allen PM, Shaw AS. A novel adapter protein orchestrates receptor patterning and cytoskeletal polarity in T cell contacts. Cell 1998 Sep 4; 94: 667-677. (PMID: 9741631)

[ii] Grakoui A, Bromley SK, Sumen C, Davis MM, Shaw AS, Allen PM, Dustin ML. 1999. The immunological synapse: A molecular machine controlling T cell activation. Science 285: 221-2

Charles A. Janeway and Ruslan Medzhitov demonstrate that human TLR4 can mediate the immune response.

Medzhitov R, Preston-Hurlburt P, Janeway CA. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 1997 Jul 24; 388: 394-397. (PMID: 9237759)

Yao-Tseng Chen, collaborating with researchers in the laboratory of Lloyd J. Old, discovers the antigen New York-ESO-1, or NY-ESO-1. The immunogenicity of NY-ESO-1 is verified by Alex Knuth and Elke Jaeger in Frankfurt.

Richard Flavell demonstrates the role of the transcription factor GATA3/STAT6 in driving the generation of Th2 type CD4+ T cells.

Zheng W, Flavell RA. The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4 T cells. Cell 1997 May 16; 89: 587-596. (PMID: 9160750)

Yongwon Choi, with Ralph Steinman and others, identifies a new tumor necrosis factor family member TRANCE (later called RANKL),[i] and subsequently demonstrates its role in the immune and bone system, and also in bone-residing cancers such as multiple myelomas.[ii]
 

[i] Wong BR, Rho J, Arron J, Robinson E, Orlinick J, Chao M, Kalachikov S, Cayani E, Bartlett III FS, Frankel WN, Lee SY, Choi Y. TRANCE is a novel ligand of the tumor necrosis factor receptor family that activates c-Jun N-terminal kinases in T cells. J Biol Chem 1997 Oct 3; 272: 25910-25914. (PMID: 9312132) Download PDF

[ii] Wong BR, Josien R, Lee SY, Sauter B, Li H-L, Steinman RM, Choi Y. TRANCE, a new TNF family member predominantly expressed in T cells, is a dendritic cell specific survival factor. J Exp Med 1997 Dec 15; 186: 2075-2080. (PMID: 9396779) Download PDF

Fuller K, Wong B, Fox S, Choi Y, Chambers TJ. TRANCE is necessary and sufficient for osteoblast-mediated activation of bone resorption in osteoclasts. J Exp Med 1998 Sep 7; 188: 997-1001. (PMID: 9730902) Download PDF

Pearse RN, Sordillo EM, Yaccoby S, Wong BR, Liau DF, Colman N, Michaeli J, Epstein J, Choi Y. Multiple myeloma disrupts the TRANCE/ osteoprotegerin cytokine axis to trigger bone destruction and promote tumor progression. Proc Natl Acad Sci U.S.A 2001 Sep 25; 98: 11581-11586. (PMID: 11562486) Download PDF

Researchers in Frankfurt, including Elke Jaeger, Dirk Jaeger, Julia Karbach, and Alex Knuth provide the first demonstration of immunoselection in vivo in the presence of antigen-specific CTLs.

Jäger E, Ringhoffer M, Altmannsberger M, Arand M, Karbach J, Jäger D, Oesch F, Knuth A. Immunoselection in vivo: independent loss of MHC class I and melanocyte differentiation antigen expression in metastatic melanoma. Int J Cancer 1997 Apr 10; 71: 142-147. (PMID: 9139833)

Dominique Bonnet and John E. Dick report the first conclusive evidence for cancer stem cells, identified in acute myelogenous leukemia (AML).

Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nature Medicine 1997 Jul; 3: 730-737. (PMID: 9212098)

Yasuaki Tamura, working with colleagues in the laboratory of Pramod Srivastava, demonstrates that tumor-derived heat shock protein-peptide vaccines can be used to treat a wide array of pre-existing tumors in mice.

Tamura Y, Peng P, Liu K, Daou M, Srivastava PK. Immunotherapy of metastatic lung cancer by heat shock protein preparations. Science 1997 Oct 3; 278: 117-120. (PMID: 9311915)

Frank Mercurio and Anjana Rao report the cloning of the IκB kinases IKK-1 and IKK-2, the essential upstream regulators of the transcription factor NFκB.

Mercurio F, Zhu H, Murray BW, Shevchenko A, Bennett BL, Li J, Young D, Barbosa M, Mann M, Manning A, Rao A. IKK-1 and IKK-2, Cytokine-activated IκB kinases essential for NF-κB activation. Science 1997 Oct 31; 278: 860-865. (PMID: 9346484)

Ira Mellman, with Ralph Steinman and others, including Shannon Turley, and Antonio Lanzavecchia provide the first clear demonstration that dendritic cells “mature” in response to microbial products or pro-inflammatory mediators, activating their antigen processing and presentation capacities. By showing that ligands associated with innate immunity enable dendritic cells to initiate T cell responses, this work provided the key missing link between the innate and adaptive immune responses.

Pierre P, Turley SJ, Gatti E, Hull M, Meltzer J, Mirza A, Inaba K, Steinman RM, Mellman I. Developmental regulation of MHC class II transport in mouse dendritic cells. Nature 1997 Aug 21; 388: 787-792. (PMID: 9285592)

Cella M, Engering A, Pinet V, Pieters J, Lanzavecchia A. Inflammatory stimuli induce accumulation of MHC class II complexes on dendritic cells.Nature 1997 Aug 1; 388: 782-787. (PMID: 9285591)

Ira Mellman, with Ralph Steinman and others, including Shannon Turley, and Antonio Lanzavecchia provide the first clear demonstration that dendritic cells “mature” in response to microbial products or pro-inflammatory mediators, activating their antigen processing and presentation capacities. By showing that ligands associated with innate immunity enable dendritic cells to initiate T cell responses, this work provided the key missing link between the innate and adaptive immune responses.

Pierre P, Turley SJ, Gatti E, Hull M, Meltzer J, Mirza A, Inaba K, Steinman RM, Mellman I. Developmental regulation of MHC class II transport in mouse dendritic cells. Nature 1997 Aug 21; 388: 787-792. (PMID: 9285592)

Cella M, Engering A, Pinet V, Pieters J, Lanzavecchia A. Inflammatory stimuli induce accumulation of MHC class II complexes on dendritic cells.Nature 1997 Aug 1; 388: 782-787. (PMID: 9285591)

Yasushi Itoh and Ronald N. Germain report studies emphasizing the hierarchical organization of T cell receptor (TCR) signaling thresholds for induction of distinct cytokine responses, and demonstrate that this threshold phenomenon applies to individual cells. The existence of such thresholds suggests that antigen dose may dictate not only the extent, but also the quality of an immune response, by altering the ratios of the cytokines produced by activated T cells.
 

Itoh Y, Germain RN. Single cell analysis reveals regulated hierarchical T cell antigen receptor signaling thresholds and intraclonal heterogeneity for individual cytokine responses of CD4+ T cells. J Exp Med 1997 Aug 29; 186: 757-676. (PMID: 9271591) Download PDF

Steve Gerondakis and colleagues establish that Rel (from the c-rel gene) in mice is a positive or negative regulator of transcription in macrophages and that Rel has distinct roles in different macrophage populations.

Grigoriadis G, Zhan Y, Grumont RJ, Metcalf D, Handman E, Cheers C, Gerondakis S. The Rel subunit of NF-kappaB-like transcription factors is a positive and negative regulator of macrophage gene expression: distinct roles for Rel in different macrophage populations. EMBO J 1996 Dec 16; 15: 7099-7107. (PMID: 9003785) Download PDF

Leslie J. Berg, Mark M. Davis, and colleauges demonstrate that a T cell receptot (TCR) binds to antagonist ligands with lower affinities and faster dissociation rates than to agonists.

Lyons DS, Lieberman SA, Hampl J, Boniface JJ, Chien Y-h, Berg LJ, Davis MM. A TCR binds to antagonist ligands with lower affinities and faster dissociation rates than to agonists. Immunity 1996 Jul; 5: 53-61. (PMID: 8758894)

Ellen V. Rothenberg and Susan B. Ward report that the interleukin-2 (IL-2) transcriptional apparatus integrates multiple types of biochemical information in determining whether or not the gene will be expressed, using multiple diverse transcription factors that are each optimally activated or inhibited by different signaling pathways.
 

Rothenberg EV, Ward SB. A dynamic assembly of diverse transcription factors integrates activation and cell-type information for interleukin 2 gene regulation. Proc Natl Acad Sci U.S.A 1996; 93: 9358-9365. (PMID: 8790334) Download PDF

Diana L. Sylvestre and Jeffrey V. Ravetch demonstrate by differential reconstitution in vivo that FcgRIII on mast cells is necessary for the inflammatory response to experimental immune complexes.

Sylvestre DL, Ravetch JV. A dominant role for mast cell Fc receptors in the Arthus reaction. Immunity 1996; 5: 387-390

Anjano Rao and colleagues find evidence in mice that transcription factor NFAT1 exerts a negative regulatory influence on the immune response.

Xanthoudakis S, Viola JPB, Shaw KTY, Luo C, Wallace JD, Bozza PT, Curran T, Rao A. An enhanced immune response in mice lacking the transcription factor NFAT1. Science 1996; 272: 892-895. (PMID: 8629027)

James P. Allison and Matthew Krummel demonstrate that a monoclonal antibody directed against the CTLA-4 molecule in a mouse model of melanoma could result in the rejection of tumors and that this rejection also resulted in immunity to a second exposure to tumor cells.

Leach DR, Krummel MF, Allison JP. Enhancement of antitumor immunity by CTLA-4 blockade. Science 1996 Mar 22; 271: 1734-1736. (PMID: 8596936)

Bruno Lemaitre and Jules A. Hoffmann demonstrate that Toll receptors in Drosophila mediate immune defense against fungal infection.
 

Lemaitre B, Nicolas E, Michaut L, Reichhart JM, Hoffmann JA. The dorsoventral regulatory gene cassette spätzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell 1996 Sep 20; 86: 973-983. (PMID: 8808632)

Andy Peters and Ursula Storb show that the initiation of Ig gene transcription targets Ig gene somatic hypermutation (SHM), by duplicating the variable (V) region promoter upstream of the constant (C) region and showing that a second wave of mutations occurs over the C region. This finding led them to propose a novel hypothesis of SHM, namely that a mutator factor (now known to be AID) loads on the transcription complex near the promoter, travels with the elongating RNA polymerase, and stochastically dissociates, thus limiting SHM to the VJ region.

Peters A, Storb U. Somatic hypermutation of immunoglobulin genes is linked to transcription initiation. Immunity 1996 Jan; 4: 57-65. (PMID: 8574852)

Storb U. Progress in understanding the mechanism of somatic hypermutation. Immunol Rev 1998 Apr; 162: 5-11. (PMID: 9602347)

Researchers in Frankfurt, including Elke Jaeger, Dirk Jaeger, Julia Karbach, and Alex Knuth demonstrate enchanced immune responses, including delayed type hypersensitivity, with GM-CSF as an adjuvant.

Jäger E, Ringhoffer M, Dienes HP, Arand M, Karbach J, Jäger D, Ilsemann C, Hagedorn M, Oesch F, Knuth A. Granulocyte-macrophage-colony-stimulating factor enhances immune responses to melanoma-associated peptides in vivo. Int J Cancer 1996 Jul 3; 67: 54-62. (PMID: 8690525)

Bjarne Bogen provides experimental evidence that antigen-specific CD4+ T cells are rendered tolerant during tumor growth in vivo.

Bogen B. Peripheral T cell tolerance as a tumor escape mechanism: deletion of CD4+ T cells specific for a monoclonal immunoglobulin idiotype secreted by a plasmacytoma. Eur J Immunol 1996 Nov; 26: 2671-2679. (PMID: 8921954)

John M. Kirkwood reports the first significant improvement of both survival and relapse-free interval for melanoma patients treated with high-dose Interferon alfa-2b (E1684).

Shimon Sakaguchi identifies regulatory T cells (CD4+CD25+) and their role in protecting against autoimmunity.

Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 1995 Aug 1; 155: 1151-1164. (PMID: 7636184) Download PDF

Gary Koretsky and colleagues report the discovery of SLP-76.
 

Jackman JK, Motto DG, Sun Q, Tanemoto M, Turck CW, Peltz GA, Koretzky GA, Findell PR. Molecular cloning of SLP-76, a 76-kDa tyrosine phosphoprotein associated with Grb2 in T cells. J Biol Chem 1995 Mar 31; 270: 7029. (PMID: 7706237) Download PDF

Marie Marchand and Thierry Boon report the first cases of clinical regressions of melanoma metastases following vaccination with a MAGE-A3 peptide.[i] Additional cases will be reported in 1999, confirming these promising clinical results.[ii]


[i] Marchand M, Weynants P, Rankin E, Arienti F, Belli F, Parmiani G, Cascinelli N, Bourlond A, Vanwijck R, Humblet Y, Canon J-L, Laurent C, Naeyaert J-M, Plagne R, Deraemaeker R, Knuth A, Jäger E, Brasseur F, Herman J, Coulie PG, Boon T. Tumor regression responses in melanoma patients treated with a peptide encoded by gene MAGE-3. Int J Cancer 1995 Dec 11; 63: 883-885. (PMID: 8847150)

[ii] Marchand M, van Baren N, Weynants P, Brichard V, Dréno B, Tessier M-H, Rankin E, Parmiani G, Arienti F, Humblet Y, Bourlond A, Vanwijck R, Liénard D, Beauduin M, Dietrich P-Y, Russo V, Kerger J, Masucci G, Jäger E, De Greve J, Atzpodien J, Brasseur F, Coulie PG, van der Bruggen P, Boon T. Tumor regressions observed in patients with metastatic melanoma treated with an antigenic peptide encoded by gene MAGE-3 and presented by HLA-A1. Int J Cancer 1999 Jan 18; 80: 219-230. (PMID: 9935203)

Pierre Coulie and Thierry Boon, and Thomas Wölfel show that human T lymphocytes recognize antigens caused by driver278 or passenger279 tumor-specific mutations.

Coulie PG, Lehmann F, Lethé B, Herman J, Lurquin C, Andrawiss M, Boon T. A mutated intron sequence codes for an antigenic peptide recognized by cytolytic T lymphocytes on a human melanoma. Proc Natl Acad Sci U.S.A 1995 Aug 15; 92: 7976-7980. (PMID: 7644523) doi: 10.1073/pnas.92.17.7976

Wölfel T, Hauer M, Schneider J, Serrano M, Wölfel C, Klehmann-Hieb E, De Plaen E, Hankeln T, Meyer zum Büschenfelde K-H, Beach D. A p16INK4a-insensitive CDK4 mutant targeted by cytolytic T lymphocytes in a human melanoma. Science 1995 Sep 1; 269: 1281-1284. (PMID: 7652577)

Arthur M. Krieg and coworkers characterize CpG oligonucleotides and discover that they are robust stimulators of immune cells. CpG oligonucleotides are TLR9 agonists and have broad therapeutic application in humans.
 

Krieg AM, Yi AK, Matson S, Waldschmidt TJ, Bishop GA, Teasdale R, Koretzky GA, Klinman DM. CpG motifs in bacterial DNA trigger direct B-cell activation. Nature 1995 Apr 6; 374: 546-549. (PMID: 7700380)

Paul Rothman demonstrates a role for JAK-STAT signaling in malignancy.

Danial N, Pernis A, Rothman P. Jak-STAT signaling induced by the v-abl oncogene. Science 1995 Sep 29; 269:1875-1877. (PMID: 7569929)

Bijay Mukherji and colleagues provide the first report on dendritic cell vaccination for cancer.

Mukherji B, Chakraborty NG, Yamasaki S, Okino T, Yamase H, Sporn JR, Kurtzman SK, Ergin MT, Ozols J, Meehan J, Mauri F. Induction of antigen-specific cytolytic T cells in situ in human melanoma by immunization with synthetic peptide-pulsed autologous antigen presenting cells. Proc Natl Acad Sci U.S.A 1995 Aug 15; 92: 8078-8082. (PMID: 7644541) Download PDF

Albert Bendelac discovers and characterizes the natural killer T (NKT) cell.
 

Bendelac A, Killeen N, Littman DR, Schwartz RH. A subset of CD4+ thymocytes selected by MHC class I molecules. Science 1994 Mar 25; 263: 1774-1778. (PMID: 7907820) Bendelac A, Lantz O, Quimby E, Yewdell JW, Bennink JR, Brutkiewicz RR. CD1 recognition by mouse NK1+ T lymphocytes. Science 1995 May 12; 268: 863-865. (PMID: 7538697)

Several families of cancer-germline genes are identified by the group of Thierry Boon, including the MAGE,[i] BAGE,[ii] and GAGE[iii] families. These genes are expressed in many tumors and are silent in normal tissues except male germline cells. Many of them encode tumor-specific antigens recognized by T lymphocytes.
 

[i] De Plaen E, Arden K, Traversari C, Gaforio JJ, Szikora J-P, De Smet C, Brasseur F, van der Bruggen P, Lethé B, Lurquin C, Brasseur R, Chomez P, De Backer O, Cavenee W, Boon T. Structure, chromosomal localization, and expression of 12 genes of the MAGE family. Immunogenetics 1994; 40: 360-369. (PMID: 7927540)

[ii] Boël P, Wildmann C, Sensi M-L, Brasseur R, Renauld J-C, Coulie P, Boon T, van der Bruggen P. BAGE, a new gene encoding an antigen recognized on human melanomas by cytolytic T lymphocytes. Immunity 1995 Feb; 2: 167-175. (PMID: 7895173)

[iii] Van den Eynde B, Peeters O, De Backer O, Gaugler B, Lucas S, Boon T. A new family of genes coding for an antigen recognized by autologous cytolytic T lymphocytes on a human melanoma. J Exp Med 1995 Sep 1; 182: 689-698. (PMID: 7544395) Download PDF

James Darnell, George Stark, and Ian Kerr report studies demonstrating the importance of interferon to elucidate signal trafficking from the cell surface to the nucleus.
 

Darnell JE, Kerr IM, Stark GR. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science 1994 Jun 3; 264: 1415. (PMID: 8197455)

Akiko Uenaka and Eiichi Nakayama identify a murine leukemia antigen recognized by cytotoxic T cells.

Uenaka A, Ono T, Akisawa T, Wada H, Yasuda T, Nakayama E. Identification of a unique antigen peptide pRL1 on BALB/c RL male 1 leukemia recognized by cytotoxic T lymphocytes and its relation to the Akt oncogene. J Exp Med 1994 Nov 1; 180: 1599-1607. (PMID: 7964448) Download PDF

Human herpesvirus 8 (HHV-8), which causes Kaposi’s sarcoma, is identified.

Benoit Van den Eynde, Pierre van der Bruggen, Béatrice Gaugler, and Thierry Boon identify gene MAGE-A3 as encoding a peptide recognized by melanoma-specific CTL. Being both tumor-specific and widely expressed in human tumors, MAGE-A3 is an ideal cancer vaccine target and will be the focus of many clinical trials, including the largest clinical trial ever conducted in lung cancer, MAGRIT, launched by GlaxoSmithKline in 2007.
 

Gaugler B, Van den Eynde B, van der Bruggen P, Romero P, Gaforio JJ, De Plaen E, Lethé B, Brasseur F, Boon T. Human gene MAGE-3 codes for an antigen recognized on a melanoma by autologous cytolytic T lymphocytes. J Exp Med 1994 Mar 1; 179: 921-930. (PMID: 8113684) Download PDF

Alex Huang and Drew Pardoll, with Elizabeth Jaffee and Hyam Levitsky at Johns Hopkins School of Medicine demonstrate tumor-associated antigen processing and presentation to CD8+ T cell by bone marrow-derived professional antigen presenting cells via “cross-priming.”

Huang AY, Golumbek P, Ahmadzadeh M, Jaffee E, Pardoll D, Levitsky H. Role of bone marrow-derived cells in presenting MHC class I-restricted tumor antigens. Science 1994 May 13; 264: 961-965. (PMID: 7513904)

Ralph Steinman and Nina Bhardwaj, independently with other laboratories, discover the plasmacytoid dendritic cell (pDC) subset in circulating blood.

O’Doherty U, Peng M, Gezelter S, Swiggard WJ, Betjes M, Bhardwaj N, Steinman RM. Human blood contains two subsets of dendritic cells, one immunologically mature and the other immature. Immunology 1994 Jul; 82: 487-493. (PMID:7525461) Download PDF

John J. O’Shea and colleagues report that a new member of the Janus family of kinases (JAK-3) is coupled to the interleukin 2 receptor (IL-2R) in human peripheral blood T cells and natural killer cells. Interaction with interleukin 2 (IL-2) leads to the phosphorylation and activation of JAK-3.

Johnston JA, Kawamura M, Kirken RA, Chen Y-Q, Blake TB, Shibuya K, Ortaldo JR, McVicar DW, O'Shea JJ. 1994. Phosphorylation and activation of the Jak-3 Janus kinase in response to interleukin-2. Nature 370: 151-3.

Ralph M. Steinman, Gerold Schuler, and colleagues find that large numbers of dendritic cells can be mobilized by specific cytokines from progenitors in the blood stream.
 

Romani N, Gruner S, Brang D, Kampgen E, Lenz A, Trockenbacher B, Konwalinka G, Fritsch PO, Steinman RM, Schuler G. Proliferating dentritic cell progenitors in human blood. J Exp Med 1994; 180: 83-93. (PMID: 8006603)

Antonio Lanzavecchia finds that efficient presentation of soluble antigen by cultured human dendritic cells is maintained by granulocyte/macrophage colony-stimulating factor plus interleukin 4 and downregulated by tumor necrosis factor alpha.

Sallusto F, Lanzavecchia A. Efficient presentation of soluble antigen by cultured human dendritic cells is maintained by granulocyte/macrophage colony-stimulating factor plus interleukin 4 and downregulated by tumor necrosis factor alpha. J Exp Med 1974 Apr 1; 179: 1109-1118. (PMID: 8145033) Download PDF

Diana L. Sylvestre and Jeffrey V. Ravetch find a murine strain deficient in Fc receptor expression could respond normally to other stimuli yet their inflammatory response to immune complexes was markedly attenuated. These results suggest that immune complex-triggered inflammation is initiated by cell bound Fc receptors and is then amplified by cellular mediators and activated complement.


Sylvestre DL, Ravetch JV. Fc receptors initiate the Arthus reaction: Redefining the inflammatory cascade. Science 1994 Aug 19; 265: 1095-1098. (PMID: 8066448)

Alan Houghton, Carl F. Nathan, and colleagues provide the first demonstration that treatment with monoclonal antibodies can lead to reproducible tumor responses in cancer patients with solid tumors.

Minasian LM, Szatrowski TP, Rosenblum M, Steffens T, Morrison ME, Chapman PB, Williams L, Nathan CF, Houghton AN. Hemorrhagic tumor necrosis during a pilot trial of tumor necrosis factor-alpha and anti-GD3 ganglioside monoclonal antibody in patients with metastatic melanoma. Blood 1994 Jan 1; 83: 56-64. (PMID: 8274754) Download PDF

Theodore S. Jardetzky is part of the team that identifies the three-dimensional crystal structure of the human class II major histocompatibility complex (MHC) in the presence of superantigen.
 

Brown JH, Jardetsky TS, Gorga JC, Stern LJ, Urban R, Strominger JL, Wiley DC. Three-dimensional structure of the human class II histocompatibility antigen HLA-DR1. Nature 1993 Jul 1; 364: 33-39. (PMID: 8316295)

Drew Pardoll, Glenn Dranoff, Elizabeth Jaffee, Hyam Levitsky, and colleagues conduct preclinical studies showing that a vaccine composed of tumor cells irradiated and genetically modified to produce immune system growth factor GM-CSF (granulocyte-macrophage colony-stimulating factor)—which would become known as the therapeutic cancer vaccine GVAX—could induce potent, specific, and long-lasting anti-tumor immunity in multiple mouse tumor models. Based on these preclinical findings, CRI provides a seed grant for a phase I clinical trial to test the strategy in patients with metastatic renal cell carcinoma. “When I began my career in cancer research in 1989, CRI was the only organization that believed in supporting junior researchers as the future of cancer immunotherapy. I had just had my NIH grant turned down and CRI gave me an investigators grant that allowed me to launch my career. They then funded a number of postdoctoral fellows, who are now themselves independent cancer immunology leaders at institutions all over the world. Without CRI, I would not be doing this today. Starting in 2010, cancer immunotherapy has emerged as the "new" breakthrough approach to cancer therapy but this is actually the fruit of decades of labor and CRI has been steadfastly behind that research from the beginning.” – Drew Pardoll


Dranoff G, Jaffee E, Lazenby A, Golumbek P, Levitsky H, Brose K, Jackson V, Hamada H, Pardoll D, and Mulligan RC. Vaccination with irradiated tumor cells engineered to secrete murine granulocyte-macrophage colony-stimulating factor stimulates potent, specific, and long-lasting anti-tumor immunity. Proc Natl Acad Sci U.S.A 1993 Apr 15; 90: 3539-3543. (PMID: 8097319). Download PDF

Anjana Rao and colleagues Jugnu Jain, Patricia McCaffrey, and Patrick Hogan report the molecular identification of the transcription factor NFAT (nuclear factor of activated T cells). They show that it is a substrate for calcineurin, the phosphatase target of the immunosuppressive drugs cyclosporin A and FK506, and that it exists in activated cells as a complex with the transcription factor AP-1 (Fos-Jun). [i] Gerald Crabtree had earlier described NFAT as an inducible, cyclosporine-sensitive DNA-binding activity in 1988.[ii]
 

[i] Jain J, McCaffrey PG, Miner Z, Kerppola TK, Lambert JN, Verdine GL, Curran T, Rao A. The T cell transcription factor NFATp is a substrate for calcineurin and interacts with the DNA-binding domains of Fos and Jun. Nature 1993; 365: 352-355. (PMID: 8397339)

McCaffrey PG, Luo C, Kerppola TK, Jain J, Badalian TM, Ho AM, Burgeon E, Lane WS, Lambert JL, Curran T, Verdine GL, Rao A, Hogan PG. Isolation of the cyclosporin-sensitive T cell transcription factor NFATp. Science 1993 Oct 29; 262: 750-754. (PMID: 8235597)

[ii] Shaw JP, Utz PJ, Durand DB, Toole JJ, Emmel EA, Crabtree GR. Identification of a putative regulator of early T cell activation genes. Science 1988 Jul 8; 241: 202-205. (PMID: 3260404) Download PDF

Kenneth M. Murphy and Anne O’Garra discover that dendritic cells and macrophages are required for T-helper 1(Th1) development of CD4+ T cells. They also determine that interleukin 12 (IL-12) substitution for macrophages to stimulate IFN-gamma production is IFN-gamma-dependent.
 

Macatonia SE, Hsieh C-S, Murphy KM, O'Garra A. Dendritic cells and macrophages are required for Th1 development of CD4+ T cells from alpha beta TCR transgenic mice IL-12 substitution for macrophages to stimulate IFN-gamma production is IFN-gammadependent. International Immunology 1993; 5: 1119-1128.

Vincent Brichard, Thomas Wölfel, and Thierry Boon identify the first CTL-defined tumor antigen derived from a melanoma differentiation protein, tyrosinase. [i] Other examples were later identified by Pierre Coulie and Thierry Boon[ii] and by Yutaka Kawakami and Steven Rosenberg.[iii]
 

[i] Brichard V, Van Pel A, Wölfel T, Wölfel C, De Plaen E, Lethé B, Coulie P, Boon T. The tyrosinase gene codes for an antigen recognized by autologous cytolytic T lymphocytes on HLA-A2 melanomas. J Exp Med 1993 Aug 1; 178: 489-495. (PMID: 8340755) Download PDF

Wölfel T, Hauer M, Klehmann E, Brichard V, Ackermann B, Knuth A, Boon T, Meyer zum Büschenfelde K-H. Analysis of antigens recognized on human melanoma cells by A2-restricted cytolytic T lymphocytes (CTL). Int J Cancer 1993 Sep 9; 55: 237-244. (PMID: 7690346)

[ii] Coulie PG, Brichard V, Van Pel A, Wölfel T, Schneider J, Traversari C, Mattei S, De Plaen E, Lurquin C, Szikora J-P, Renauld J-C, Boon T. A new gene coding for a differentiation antigen recognized by autologous cytolytic T lymphocytes on HLA-A2 melanomas. J Exp Med 1994 Jul 1; 180: 35-42. (PMID: 8006593) Download PDF

[iii] Kawakami Y, Eliyahu S, Delgado CH, Robbins PF, Rivoltini L, Topalian SL, Miki T, Rosenberg SA. Cloning of the gene coding for a shared human melanoma antigen recognized by autologous T cells infiltrating into tumor. Proc Natl Acad Sci U.S.A 1994 Apr 26; 91: 3515-3519. (PMID: 8170938) Download PDF

Lorenzo Moretta and colleagues report on the identification of the first inhibitory receptors on human natural killer cells.

Moretta A, Vitale M, Bottino C, Orengo AM, Morelli L, Augugliaro R, Barbaresi M, Ciccone E, Moretta L. P58 molecules as putative receptors for major histocompatibility complex (MHC) class I molecules in human natural killer (NK) cells: anti-p58 antibodies reconstitute lysis of MHC class I-protected cells in NK clones displaying different specificities. J Exp Med 1993 Aug 1; 178: 597-604. (PMID: 8340759) Download PDF

Giorgio Parmiani and colleagues are the first to unequivocally demonstrate that human melanoma antigens recognized by patient T cells include molecules belonging to the normal melanocyte lineage. These antigens were molecularly defined the following year both by Steve A. Rosenberg (named MART-1) at the National Cancer Institute and Thierry Boon (named Melan-A) at the LICR Brussels Branch. The discovery that lineage-related melanoma antigens can be recognized by patients’ T cells then opened the way to their use in melanoma immunotherapy. (PMID: 8459226)

Don Hunt and Victor Engelhard report the first characterization of peptides from an MHC class I molecule by mass spectrometry.

Hunt DF, Henderson RA, Shabanowitz J, Sakaguchi K, Michel H, Sevilir N, Cox AL, Appella E, Engelhard VH. Characterization of peptides bound to the class I MHC molecule HLA-A2.1 by mass spectrometry. Science 1992 Mar 6; 255: 1261-1263. (PMID: 1546328) Download PDF

Luc Van Kaer, with Hidde Ploegh and sponsor Susumu Tonegawa, demonstrates a critical role of the TAP pathway for class I-restricted antigen presentation in vivo.”

Van Kaer L, Ashton-Richardt PG, Ploegh HL, Tonegawa S. TAP1 mutant mice are deficient in antigen presentation, surface class I molecules, and CD4-8+ T cells. Cell 1992 Dec 24; 71: 1205-1214. (PMID: 1473153)

Arthur Weiss and colleagues report the discovery of ZAP-70 and its association with the T cell receptor following activation.

Chan AC, Iwashima M, Trck CW, Weiss A. ZAP-70: a 70kd protein-tyrosine kinase that associates with the TCRzeta chain. Cell 1992 Nov 13; 71: 649-662. (PMID: 1423621)

Ferdy Lejeune and colleagues report the first study of isolated limb perfusion with tumor necrosis factor in patients with melanoma and sarcoma.

Lienard D, Ewalenko P, Delmotte JJ, Renard N, and Lejeune FJ. High-dose recombinant tumor necrosis factor alpha in combination with interferon gamma and melphalan in isolation perfusion of the limbs for melanoma and sarcoma. J Clin Oncol 1992 Jan; 10: 52-60. (PMID: 1727926)

Xin-Yuan Fu and James E. Darnell, Jr. report the discovery of the STAT gene family and the cloning of the first two STAT family members (STAT1 and STAT2). The discovery of the STAT pathway was cited as one of the 10 major breakthroughs of the year by Science, and the STAT pathway is known now as a major pathway involved in immunity control, development, and cancer pathogenesis. 

Fu X-Y, Schindler C, Improta T, Aebersold R, Darnell JE. The proteins of ISGF3, the IFN-alpha induced transcriptional activator, define a gene family involved in signal transdution. Proc Natl Acad Sci U.S.A 1992 Aug 15; 89: 7840-7843. (PMID: 1502204) Download PDF
 

James Allison and David Raulet (also Jane A. Gross, 1991-1994 CRI Fellow with Roger Perlmutter) demonstrate that blocking CD28 hampers T cell activation by antigen presenting cells and antigen.

Harding FA, McArthur JG, Gross JA, Raulet DH, Allison JP. CD28-mediated signaling co-stimulates murine T cells and prevents induction of anergy in T-cell clones. Nature 1992 Apr 16; 356: 607-609. (PMID: 1313950)

Jeffrey Bluestone and colleagues provide the first demonstration of tolerance induction by costimulation blockade. These studies, showing the functional effects of CTLA-4 Ig as a potential tolerogen, led to the discovery of CD86 and the development of the first costimulation blockade (Abatecept).

Larry Samelson and colleagues demonstrate that CD4 is coupled to the tyrosine kinase LCK.
 

Veillette A, Bookman MA, Horak EM, Samelson LE, Bolen JB. Signal transduction through the T-lymphocyte CD4 receptor involves the activation of the internal membrane tyrosine-protein kinase p56lck. Nature 1989 Mar 16; 338: 257-259. (PMID: 2784195)
 

Carl June, Craig B. Thompson, and colleagues demonstrate the role of CD28 in T cell costimulation.

Thompson CV, Lindsten T, Ledbetter JA, Kunkel SL, Young SA, Emerson SG, Leiden JM, June CL. CD28 activation pathway regulates the production of multiple T-cell-derived lymphokines/cytokines. Proc Natl Acad Sci U.S.A 1989 Feb; 86: 1333-1337. (PMID: 2465550) Download PDF

Zelig Eshhar and colleagues first use the T-body approach, employing chimeric receptors composed of an antibody recognition unit linked to T cell activation domains, to redirect T cells to recognize and attack tumor cells.
 

Gross G, Waks T, Eshhar Z. Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity (chimeric genes/antibody variable region). Proc Natl Acad Sci U.S.A 1989 Dec; 86: 10024-10028. (PMID: 2513569) Download PDF

Giorgio Trinchieri and his team at the Wistar Institute identify interleukin-12 (IL-12), a cytokine that helps regulate the body’s resistance to infections and cancer.

Kobayashi M, Fitz L, Ryan M, Hewick RM, Clark SC, Chan S, Loudon R, Sherman F, Perussia B, Trinchieri G. Identification and purification of natural killer cell stimulatory factor (NKSF), a cytokine with multiple biologic effects on human lymphocytes. J Exp Med 1989 Sep 1; 170: 827-845. (PMID: 2504877) Download PDF

Bert Vogelstein and colleagues find that mutations in the p53 gene play a role in the development of many common human cancers.
 

Nigro JM, Baker SJ, Preisinger AC, Jessup JM, Hostetter R, Cleary K, Bigner SH, Davidson N, Baylin S, Devilee P, Glover T, Collins FS, Weslon A, Modali R, Harris CC, Vogelstein B. Mutations in the p53 gene occur in diverse human tumour types. Nature 1989 Dec 7; 342: 705-708. (PMID: 2531845)

Pramod Srivastava and Lloyd J. Old identify the human homologue of the mouse tumor rejection antigen gp96.

Srivastava PK, Old LJ. Identification of the human homologue of the murine tumor rejection antigen gp96. Cancer Res 1989 Mar 15; 49: 1341-1343. (PMID: 2924290) Download PDF

Irving L. Weissman and colleagues are the first to isolate hematopoietic stem cells in mice.
 

Spangrude GJ, Heimfeld S, Weissman IL. Purification and characterization of mouse hematopoietic stem cells. Science 1988 Jul 1; 241: 58-62. (PMID: 2898810)

The cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is identified.

Brunet JF, Denizot F, Luciani MF, Roux-Dosseto M, Suzan M, Mattei MG, Golstein P. A new member of the immunoglobulin superfamily--CTLA-4. Nature 1987 Jul 16-22; 328: 267-270. (PMID: 3496540)

Carolyn Doyle and Jack Strominger provide the first direct evidence that CD4 bound to MHC class II and that this interaction could mediate cell adhesion.

Doyle C, Strominger JL. Interaction between CD4 and class II MHC molecules mediates cell adhesion. Nature 1987 Nov 19-25; 330: 256-259. (PMID: 2823150) Download PDF
 

Alain R. Townsend and Andrew J. McMichael demonstrate that peptide length is a factor contributing to recognition of antigen by CD8+ T lymphocytes, specifically that MHC class I molecules bind short peptides.
 

Townsend ARM, Rothbard J, Gotch FM, Bahadur G, Wraith D, McMichael AJ. The epitopes of influenza nucleoprotein recognized by cytotoxic T lymphocytes can be defined with short synthetic peptides. Cell 1986 Mar 28; 44: 959–968. (PMID: 2420472)

Timothy Mosmann and Robert Coffman propose the Th1/Th2 model of T helper cell function. Th1 cells produce interferon-gamma, which plays an important role in anti-tumor immunity and in defending against intracellular pathogens, whereas Th2 cells generate IL-4, IL-5, and IL-13, which protect against parasitic infections and help mediate antibody responses.
 

Mosmann TR, Cherwinski H, Bond MW, Giedlin MA, Coffman RL. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol 1986 Apr 1; 136: 2348-2357. (PMID: 2419430) Download PDF

Two groups, led by Frank Lee at DNAX Research Institute[i] and by Tasuku Honjo at Kyoto University,[ii] clone the gene encoding for IL-4.

[i] Lee F, Yokota T, Otsuka T, Meyerson P, Meyerson P, Villaret D, Coffman D, Mosmann T, Rennick D, Roehm N, Smith C, Zlotnick A, Arai K-I. Isolation and characterization of a mouse interleukin cDNA clone that expresses B-cell stimulatory factor activities and T-cell and mast cell-stimulating activities. Proc Natl Acad Sci U.S.A 1986 Apr; 83: 2061-2065. (PMID: 3083412) Download PDF

[ii] Noma Y, Sideras T, Naito T, Bergstedt-Lindqvist S, Azuma C, Severinson E, Takabe T, Kinashi K, Matsuda F, Yaoita Y, Honjo T. Cloning of cDNA encoding the murine IgG1 induction factor by a novel strategy using SP6 promoter. Nature 1986 Feb 20-26; 319: 640-646. (PMID: 3005865)

Richard Axel and colleagues, including Leonard Chess and Dan Littman, identify T4 (CD4) as the molecule that enables HIV to enter immune system cells.

McDougal JS, Maddon PJ, Dalgliesh AG, Clapham PR, Littman DR, Godfrey M, Maddon DE, Chess L, Weiss RA, Axel R. 1986. The T4 glycoprotein is a cell-surface receptor for the AIDS virus. Cold Spring Harbor Symp Quant Biol 1986; 51 (pt. 2): 703-711. (PMID: 3495395)

Larry Samelson provides the first demonstration that the TCR is coupled to tyrosine kinase pathways, now known to be true for all immunoreceptors.

Samelson LE, Patel MD, Weissman AM, Harford JB, Klausner RD. Antigen activation of murine T cells induces tyrosine phosphorylation of a polypeptide associated with the T cell antigen receptor. Cell 1986 Sep 26; 46: 1083-1090. (PMID: 2428504)

Klas Kärre, with Rolf Kiessling, reports on experiments suggesting that natural killer cells are inhibited, not activated, by interacting with MHC class I.
 

Kärre K, Ljunggren HG, Piontek G, Kiessling R. Selective rejection of H-2-deficient lymphoma variants suggests alternative immune defence strategy. Nature 1986 Feb 20-26; 391: 675-678. (PMID: 3951539) Download PDF
 

Steven Rosenberg and colleagues report anti-tumor responses in 3 of 10 patients treated with high-dose interleukin-2 alone.

Lotze MT, Chang AE, Seipp CA, Simpson C, Vetto JT, Rosenberg SA. High-dose recombinant interleukin 2 in the treatment of patients with disseminated cancer. Responses, treatment-related morbidity, and histologic findings. JAMA 1986 Dec 12; 256: 3117-3124. (PMID: 3491225)
 

Timothy Springer, with colleagues Michael L. Dustin and Charles A. Dinarello, identifies and characterizes adhesion molecules, a class of cell surface proteins that function in the interactions of immune cells with other cells, including antigen-specific recognition and cell trafficking: integrin LFA-1 involved in cytoskeleton and signaling, and intracellular adhesion molecules (ICAMs), which are binding partners (ligands) for LFA-1 and are increased in inflammatory and autoimmune disease.
 

Dustin ML, Rothlein R, Bhan AK, Dinarello CA, Springer TA. Induction by IL 1 and interferon-gamma: tissue distribution, biochemistry, and function of a natural adherence molecule (ICAM-1). J Immunol 1986 Jul 1; 137: 245–254. (PMID: 3086451) Download PDF

Rothlein R, Dustin ML, Marlin SD, Springer TA. A human intercellular adhesion molecule (ICAM-1) distinct from LFA-1. J Immunol 1986 Aug 15; 137: 1270–1274. (PMID: 3525675) Download PDF

Susumu Tonegawa, Leroy Hood, and colleagues report on the organization of immunoglobulin genes, demonstrating how so many antibody patterns can be produced by such a limited number of genes. These ideas were also very important in understanding the structure and formation of the T cell receptor.

Eiichi Nakayama and Akiko Uenaka report in vivo depletion of CD8 T cells by administrating an anti-Lyt antibody. The method became widely used to dissect T cell responses in vivo.

Nakayama E, Uenaka A. Effect of in vivo administration of Lyt antibodies. Lyt phenotype of T cells in lymphoid tissues and blocking of tumor rejection. J Exp Med 1985 Feb 1; 161: 345-355. (PMID: 3871834) Download PDF
 

Bruce Beutler and Anthony Cerami provide the first demonstration of the role of tumor necrosis factor in the pathogenesis of disease.

Beutler B, Milsark IW, Cerami AC. Passive immunization against cachectin/tumor necrosis factor protects mice from lethal effects of endotoxin. Science 1985 Aug 30; 229: 869-871. (PMID: 3895437) (Pillars)

Emil Unanue and colleagues demonstrate that a processed peptide can bind to an MHC molecule directly, establishing the role of the MHC molecule in antigen processing and presentation.
 

Babbitt BP, Allen PM, Matsueda G, Haber E, Unanue ER. Binding of immunogenic peptides to Ia histocompatibility molecules. Nature 1985 Sep 26; 317: 359-361. (PMID: 3876313) (Pillars)

Transforming growth factor beta (TGF-beta) is identified and cloned by Rik Derynck and colleagues.

Derynck R, Jarrett JA, Chen EY, Eaton DH, Bell JR, Assoian RK, Roberts AB, Sporn MB, Goeddel DV. Human transforming growth factor-beta complementary DNA sequence and expression in normal and transformed cells. Nature 1985 Aug 22; 316: 701. (PMID: 3861940)
 

Larry Samelson, Richard D. Klausner, and associates report the characterization of the full TCR complex and discovery of the TCR zeta chain.


Samelson LE, Harford JB, Klausner RD. Identification of the components of the murine T cell antigen receptor complex. Cell 1985 Nov; 43: 223-231. (PMID: 3878228)

Researchers in the laboratory of Richard A. Axel, including Leonard Chess and Dan Littman, clone the genes for the CD4[i] and CD8[ii] T cell surface proteins.
 

[i] Maddon PJ, Littman DR, Godfrey M, Maddon DE, Chess L, Axel R. The isolation and nucleotide sequence of a cDNA encoding the T cell surface protein T4: a new member of the immunoglobulin gene family. Cell 1985 Aug; 42: 93-104. (PMID: 2990703)

[ii] Littman DR, Thomas Y, Maddon PJ, Chess L, Axel R. The isolation and sequence of the gene encoding T8: a molecule defining functional classes of T lymphocytes. Cell 1985 Feb; 40: 237-246. (PMID: 3871356)

Pramod Srivastava and M.R. Das identify the gp100 molecule as an individually specific tumor rejection antigen of a rat hepatoma. This molecule, belonging to the gp96 family, is the first heat shock protein identified as a tumor rejection antigen.
 

Srivastava PK, MR Das. The serologically unique cell surface antigen of Zajdela ascitic hepatoma is also its tumor-associated transplantation antigen. Int J Cancer 1984 Mar 15; 33: 417-422. (PMID: 6698641)
 

Edward Creagan and John M. Kirkwood commence the first rigorous adjuvant trials of recombinant interferons for resectable melanoma.

Kirkwood JM, Ernstoff MS, Davis CA, Reiss M, Ferraresi R, Rudnick SA. Comparison of intramuscular and intravenous recombinant alpha-2 interferon in melanoma and other cancers. Ann Intern Med 1985 Jul; 103: 32-36. (PMID: 4003987)

Researchers demonstrate that IL-2 is also a growth factor for B cells.
 

Zubler RM, Lowenthal JW, Erard F, Hashimoto N, Devos R, MacDonald HR. Activated B cells express receptors for and proliferate in response to pure IL-2. J Exp Med 1984 Oct 1; 160: 1170-1183. (PMID: 6434689)

Arthur Weiss and colleagues demonstrate that T cell receptor engagement triggers elevation of cytoplasmic calcium in T cells.
 

Weiss A, Imboden J, Shoback D, Stobo J. Role of T3 surface molecules in human T-cell activation: T3-dependent activation results in an increase in cytoplasmic free calcium. Proc Natl Acad Sci U.S.A 1984 Jul; 81: 4169-4173. (PMID: 6234599) Download PDF
 

At the 4th International Lymphokine Workshop, the cloning of several cytokines is reported, including: the first of three chains in the IL-2 receptor, IL-2R-alpha, by Warren Leonard and colleagues[i]; the first haematopoietic growth factor IL-3 (multi-CSF), by the laboratory of Ian G. Young in Australia[ii]; GM-CSF by Antony Burgess, Ashley Dunn, and Nicholas Gough at the LICR Melbourne Branch[iii]; M-CSF by Ernest Kawasaki and colleagues[iv]; and G-CSF by Lawrence Souza and colleagues[v] and, independently, by Shigekazu Nakata and colleagues.[vi]
 

[i] Leonard WJ, Depper JM, Crabtree GR, Rudikoff S, Pumphrey J, Robb RJ, Krönke, Svetlik PB, Peffer NJ, Waldmann TA. Molecular cloning and expression of cDNAs for the human interleukin-2 receptor. Nature 1984 Oct 18-24; 311: 626-631. (PMID: 6090948)

[ii] Fung MC, Hapel AJ, Ymer S, Cohen DR, Johnson RM, Campbell HD, Young IG. Molecular cloning of cDNA for murine interleukin-3. Nature 1984 Jan 19-25; 307: 233-237. (PMID: 6420702)

[iii] Gough NM, Gough J, Metcalf D, Kelso A, Grail D, Nicola NA, Burgess AW, Dunn AR. Molecular cloning of cDNA encoding a murine haematopoietic growth regulator, granulocyte-macrophage colony stimulating factor. Nature 1984 Jun 28; 309: 763-767. (PMID: 6610831)

[iv] Kawasaki ES, Ladner MB, Wang AM, Van Arsdell J, Warren MK, Coyne MY, Schweickart VL, Lee MT, Wilson KJ, Boosman A...Mark DF. Molecular cloning of a complementary DNA encoding human macrophage-specific colony-stimulating factor (CSF-1). Science 1985 Oct 18; 230: 291-296. (PMID: 2996129)

[v] Souza LM, Boone TC, Gabrilove J, Lai PH, Zsebo KM, Murdock DC, Chazin VR, Bruszewski J, Lu H, Chen KK et. al. Recombinant human granulocyte colony-stimulating factor: effects on normal and leukemic myeloid cells. Science 1986 Apr 4; 232: 61-65. (PMID: 2420009)

[vi] Nakata S, Tsuchiya M, Asano S, Kaziro Y, Yamazaki T, Yamamoto O, Hirata Y, Kubota N, Oheda M, Nomura H, Ono M. Molecular cloning and expression of cDNA for human granulocyte colony-stimulating factor. Nature 1986 Jan 30; 319: 415-418. (PMID: 3484805)

Doreen Cantrell and Kendall A. Smith report the first single cell analysis of lymphocyte proliferation.

Cantrell DA, Smith KA. The interleukin-2 T-cell system: a new cell growth model. Science 1984 Jun 22; 224: 1312-1316. (PMID: 6427923)

Kin Ritchie, Ralph Brinster, and Ursula Storb show that an IgL transgene inhibits rearrangement of endogenous IgL genes, providing the first clue for the mechanism of allelic exclusion of Ig genes.
 

Ritchie KA, Brinster RL, Storb U. Allelic exclusion and control of endogenous immunoglobulin gene rearrangement in k transgenic mice. Nature 1984 Dec 6; 312: 517-520. (PMID: 6438533)
 

Catherine Uyttenhove and Thierry Boon show that immune escape of mouse tumors is due to antigen-loss variants rather than immunosuppression, experimentally validating the concept of cancer immunosurveillance.

Uyttenhove C, Maryanski J, Boon T. Escape of mouse mastocytoma P815 after nearly complete rejection is due to antigen-loss variants rather than immunosuppression. J Exp Med 1983 Mar 1; 157: 1040-1052. (PMID: 6187879) DOI: 10.1084/jem.157.3.1040

Ellis Reinherz and Stuart F. Schlossman report the identification of the TCR protein and are the first to link it to the CD3 complex.

Meuer SC, Fitzgerald KA, Hussey RE, Hodgdon JC, Schlossman SF, Reinherz EL. Clonotypic structures involved in antigen-specific human T cell function: Relationship to the T3 complex. J Exp Med 1983 Feb 1; 157: 705-719. (PMID: 6185617) DOI: 10.1084/jem.157.2.705

Françoise Barré-Sinoussi, Jean-Claude Chermann, and Luc Montagnier isolate a new retrovirus, named lymphadenopathy associated virus (LAV, now known as human immunodeficiency virus, HIV), as the cause of AIDS.
 

Barré-Sinoussi F, Chermann JC, Rey F, Nugeyre MT, Chamaret S, Gruest J, Dauguet C, Axler-Blin C, Vézinet-Brun F, Rouzioux C, Rozenbaum W, Montagnier L. Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS). Science 1983 May 20; 220: 868-871. (PMID: 6189183)
 

Tadatsugu Taniguchi and collaborators report the cloning of IL-2.

Taniguchi T, Matsui H, Fujita T, Takaoka C, Kashmina N, Yoshimoto R, Hamuro J. Structure and expression of a cloned cDNA for human interleukin-2. Nature 1983 Mar 24; 302: 305-310. (PMID: 6403867)

A team of researchers including Philippa Marrack, John Kappler, and James P. Allison provides conclusive evidence for the identification of the T cell antigen receptor (TCR).
 

Kappler J, Kubo R, Haskins K, Hannum C, Marrack P, Pigeon M, McIntyre B, Allison J, Trowbridge I. The major histocompatibility complex-restricted antigen receptor on T cells in mouse and man: identification of constant and variable peptides. Cell 1983 Nov; 35: 295-302. (PMID: 6605199) Download PDF