Photo of Kai W. Wucherpfennig,  MD, PhD

Kai W. Wucherpfennig, MD, PhD

Dana-Farber Cancer Institute

Dana-Farber Cancer Institute
Phone: (617) 632-3086

Kai W. Wucherpfennig, MD, PhD

Dana-Farber Cancer Institute


  • Professor, Neurology, Harvard Medical School
  • Chair, Cancer Immunology and Virology, Dana-Farber Cancer Institute



  • Member, Center Scientific Council

Research Abstract

T cells play a central role in cancer immunotherapy. They have the ability to specifically detect and selectively destroy cancer cells following recognition of a tumor antigen. We work on the mechanisms that constrain the activity of cytotoxic T cells in the tumor microenvironment. Using an in vivo shRNA screen, we have identified a series of negative regulators of T cell function in tumors. Our work focuses on the molecular mechanisms by which these genes inhibit T cell function against tumors and the development of novel cancer immunotherapies based on this insights.


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  • Reardon DA, Freeman G, Wu C, Chiocca EA, Wucherpfennig KW, Wen PY, Fritsch EF, Curry WT, Sampson JH, Dranoff G. Immunotherapy advances for glioblastoma. 2014; 16:1441-1458. PubMed
  • Cremasco V, Woodruff MC, Onder L, Cupovic J, Nieves-Bonilla JM, Schildberg FA, Chang J, Cremasco F, Harvey CJ, Wucherpfennig K, Ludewig B, Carroll MC, Turley SJ. B cell homeostasis and follicle confines are governed by fibroblastic reticular cells. Nat Immunol 2014; 15:973-81. PubMed
  • Sollid LM, Pos W, Wucherpfennig KW. Molecular mechanisms for contribution of MHC molecules to autoimmune diseases. Curr Opin Immunol 2014; 31C:24-30. PubMed
  • Elpek KG, Cremasco V, Shen H, Harvey CJ, Wucherpfennig KW, Goldstein DR, Monach PA, Turley SJ. The tumor microenvironment shapes lineage, transcriptional, and functional diversity of infiltrating myeloid cells. Cancer Immunol Res 2014. PubMed
  • Bettini ML, Guy C, Dash P, Vignali KM, Hamm DE, Dobbins J, Gagnon E, Thomas PG, Wucherpfennig KW, Vignali DA. Membrane Association of the CD3竜 Signaling Domain Is Required for Optimal T Cell Development and Function. J Immunol 2014. PubMed
  • Birnbaum ME, Mendoza JL, Sethi DK, Dong S, Glanville J, Dobbins J, Ozkan E, Davis MM, Wucherpfennig KW, Garcia KC. Deconstructing the Peptide-MHC Specificity of T Cell Recognition. Cell 2014; 157:1073-87. PubMed
  • Choudhuri K, Llodrá J, Roth EW, Tsai J, Gordo S, Wucherpfennig KW, Kam LC, Stokes DL, Dustin ML. Polarized release of T-cell-receptor-enriched microvesicles at the immunological synapse. Nature 2014; 507:118-23. PubMed
  • Zhou P, Shaffer DR, Alvarez Arias DA, Nakazaki Y, Pos W, Torres AJ, Cremasco V, Dougan SK, Cowley GS, Elpek K, Brogdon J, Lamb J, Turley SJ, Ploegh HL, Root DE, Love JC, Dranoff G, Hacohen N, Cantor H, Wucherpfennig KW. In vivo discovery of immunotherapy targets in the tumour microenvironment. Nature 2014; 506:52-7. PubMed
  • Pos W, Sethi DK, Wucherpfennig KW. Mechanisms of peptide repertoire selection by HLA-DM. Trends Immunol 2013; 34:495-501. PubMed
  • Harvey CJ, Wucherpfennig KW. Cracking the code of human T-cell immunity. Nat Biotechnol 2013; 31:609-10. PubMed
  • Reardon DA, Wucherpfennig KW, Freeman G, Wu CJ, Chiocca EA, Wen PY, Curry WT, Mitchell DA, Fecci PE, Sampson JH, Dranoff G. An update on vaccine therapy and other immunotherapeutic approaches for glioblastoma. 2013; 12:597-615. PubMed
  • Sethi DK, Gordo S, Schubert DA, Wucherpfennig KW. Crossreactivity of a human autoimmune TCR is dominated by a single TCR loop. Nat Commun 2013; 4:2623. PubMed
  • Pos W, Sethi DK, Call MJ, Schulze MS, Anders AK, Pyrdol J, Wucherpfennig KW. Crystal structure of the HLA-DM-HLA-DR1 complex defines mechanisms for rapid peptide selection. Cell 2012; 151:1557-68. PubMed
  • Acton SE, Astarita JL, Malhotra D, Lukacs-Kornek V, Franz B, Hess PR, Jakus Z, Kuligowski M, Fletcher AL, Elpek KG, Bellemare-Pelletier A, Sceats L, Reynoso ED, Gonzalez SF, Graham DB, Chang J, Peters A, Woodruff M, Kim YA, Swat W, Morita T, Kuchroo V, Carroll MC, Kahn ML, Wucherpfennig KW, Turley SJ. Podoplanin-rich stromal networks induce dendritic cell motility via activation of the C-type lectin receptor CLEC-2. Immunity 2012; 37:276-89. PubMed
  • Wucherpfennig KW, Sethi D. T cell receptor recognition of self and foreign antigens in the induction of autoimmunity. Semin Immunol 2011; 23:84-91. PubMed
  • Lv H, Havari E, Pinto S, Gottumukkala RV, Cornivelli L, Raddassi K, Matsui T, Rosenzweig A, Bronson RT, Smith R, Fletcher AL, Turley SJ, Wucherpfennig K, Kyewski B, Lipes MA. Impaired thymic tolerance to 留-myosin directs autoimmunity to the heart in mice and humans. J Clin Invest 2011. PubMed
  • Sethi DK, Schubert DA, Anders AK, Heroux A, Bonsor DA, Thomas CP, Sundberg EJ, Pyrdol J, Wucherpfennig KW. A highly tilted binding mode by a self-reactive T cell receptor results in altered engagement of peptide and MHC. J Exp Med 2011; 208:91-102. PubMed
  • Anders AK, Call MJ, Schulze MS, Fowler KD, Schubert DA, Seth NP, Sundberg EJ, Wucherpfennig KW. HLA-DM captures partially empty HLA-DR molecules for catalyzed removal of peptide. Nat Immunol 2010; 12:54-61. PubMed
  • Wucherpfennig KW. The first structures of T cell receptors bound to peptide-MHC. J Immunol 2010; 185:6391-3. PubMed
  • Call ME, Wucherpfennig KW, Chou JJ. The structural basis for intramembrane assembly of an activating immunoreceptor complex. Nat Immunol 2010; 11:1023-9. PubMed
  • Wucherpfennig KW, Gagnon E, Call MJ, Huseby ES, Call ME. Structural biology of the T-cell receptor: insights into receptor assembly, ligand recognition, and initiation of signaling. Cold Spring Harb Perspect Biol 2010; 2:a005140. PubMed
  • Wucherpfennig KW, Call MJ, Deng L, Mariuzza R. Structural alterations in peptide-MHC recognition by self-reactive T cell receptors. Curr Opin Immunol 2009; 21:590-5. PubMed
  • Wucherpfennig KW, Gagnon E. Positively selecting peptides: their job does not end in the thymus. Nat Immunol 2009; 10:1143-4. PubMed
  • McLaughlin KA, Chitnis T, Newcombe J, Franz B, Kennedy J, McArdel S, Kuhle J, Kappos L, Rostasy K, Pohl D, Gagne D, Ness JM, Tenembaum S, O'Connor KC, Viglietta V, Wong SJ, Tavakoli NP, de Seze J, Idrissova Z, Khoury SJ, Bar-Or A, Hafler DA, Banwell B, Wucherpfennig KW. Age-dependent B cell autoimmunity to a myelin surface antigen in pediatric multiple sclerosis. J Immunol 2009; 183:4067-76. PubMed
  • Call MJ,Xing X,Cuny GD,Seth NP,Altmann DM,Fugger L,Krogsgaard M,Stein RL,Wucherpfennig KW. In vivo enhancement of peptide display by MHC class II molecules with small molecule catalysts of peptide exchange. J Immunol 2009; 182:6342-52. PubMed
  • Xu C,Gagnon E,Call ME,Schnell JR,Schwieters CD,Carman CV,Chou JJ,Wucherpfennig KW. Regulation of T cell receptor activation by dynamic membrane binding of the CD3epsilon cytoplasmic tyrosine-based motif. Cell 2008; 135:702-13. PubMed
  • Verginis P, McLaughlin KA, Wucherpfennig KW, von Boehmer H, Apostolou I. Induction of antigen-specific regulatory T cells in wild-type mice: visualization and targets of suppression. Proc Natl Acad Sci U S A 2008; 105:3479-84. PubMed
  • Nose H, Kubota R, Seth NP, Goon PK, Tanaka Y, Izumo S, Usuku K, Ohara Y, Wucherpfennig KW, Bangham CR, Osame M, Saito M. Ex vivo analysis of human T lymphotropic virus type 1-specific CD4+ cells by use of a major histocompatibility complex class II tetramer composed of a neurological disease-susceptibility allele and its immunodominant peptide. J Infect Dis 2008; 196:1761-72. PubMed
  • Wucherpfennig KW, Allen PM, Celada F, Cohen IR, De Boer R, Garcia KC, Goldstein B, Greenspan R, Hafler D, Hodgkin P, Huseby ES, Krakauer DC, Nemazee D, Perelson AS, Pinilla C, Strong RK, Sercarz EE. Polyspecificity of T cell and B cell receptor recognition. Semin Immunol 2007; 19:216-24. PubMed
  • Grotenbreg GM, Nicholson MJ, Fowler KD, Wilbuer K, Octavio L, Yang M, Chakraborty AK, Ploegh HL, Wucherpfennig KW. Empty class II major histocompatibility complex created by peptide photolysis establishes the role of DM in peptide association. J Biol Chem 2007; 282:21425-36. PubMed
  • Garibyan L, Lobito AA, Siegel RM, Call ME, Wucherpfennig KW, Geha RS. Dominant-negative effect of the heterozygous C104R TACI mutation in common variable immunodeficiency (CVID). J Clin Invest 2007; 117:1550-7. PubMed
  • Lu L, Ikizawa K, Hu D, Werneck MB, Wucherpfennig KW, Cantor H. Regulation of Activated CD4(+) T Cells by NK Cells via the Qa-1-NKG2A Inhibitory Pathway. Immunity 2007; 26:593-604. PubMed
  • O'Connor KC, McLaughlin KA, De Jager PL, Chitnis T, Bettelli E, Xu C, Robinson WH, Cherry SV, Bar-Or A, Banwell B, Fukaura H, Fukazawa T, Tenembaum S, Wong SJ, Tavakoli NP, Idrissova Z, Viglietta V, Rostasy K, Pohl D, Dale RC, Freedman M, Steinman L, Buckle GJ, Kuchroo VK, Hafler DA, Wucherpfennig KW. Self-antigen tetramers discriminate between myelin autoantibodies to native or denatured protein. Nat Med 2007; 13:211-7. PubMed
  • Feng J, Call ME, Wucherpfennig KW. The assembly of diverse immune receptors is focused on a polar membrane-embedded interaction site. PLoS Biol 2006; 4:e142. PubMed
  • Nicholson MJ, Moradi B, Seth NP, Xing X, Cuny GD, Stein RL, Wucherpfennig KW. Small molecules that enhance the catalytic efficiency of HLA-DM. J Immunol 2006; 176:4208-20. PubMed
  • Panoutsakopoulou V, Huster KM, McCarty N, Feinberg E, Wang R, Wucherpfennig KW, Cantor H. Suppression of autoimmune disease after vaccination with autoreactive T cells that express Qa-1 peptide complexes. J Clin Invest 2004; 113:1218-24. PubMed
  • Lu L, Ikizawa K, Hu D, Werneck MBF, Wucherpfennig KW, Cantor H. Regulation of activated CD4+ T cells by NK cells via the Qa-1-NKG2A inhibitory pathway. Immunity 2008; 26:593-604.