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_wucherpfennig@dfci.harvard.edu

Kai W. Wucherpfennig, MD, PhD

Dana-Farber Cancer Institute

EDUCATIONAL TITLES

  • Professor, Neurology, Harvard Medical School
  • Professor and Co-chair, Cancer Immunology & AIDS, Dana-Farber Cancer Institute

DF/HCC PROGRAM AFFILIATION

DF/HCC ASSOCIATIONS

  • 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.

Publications

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  • 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
  • Seth N, Kaufmann D, Lahey T, Rosenberg ES, Wucherpfennig KW. Expansion and contraction of HIV-specific CD4 T cells with short bursts of viremia, but physical loss of the majority of these cells with sustained viral replication. J Immunol 2005; 175:6948-58. PubMed
  • Reddy J, Waldner H, Zhang X, Illes Z, Wucherpfennig KW, Sobel RA, Kuchroo VK. Cutting edge: CD4+CD25+ regulatory T cells contribute to gender differences in susceptibility to experimental autoimmune encephalomyelitis. J Immunol 2005; 175:5591-5. PubMed
  • Nicholson MJ, Hahn M, Wucherpfennig KW. Unusual features of self-peptide/MHC binding by autoimmune T cell receptors. Immunity 2005; 23:351-60. PubMed
  • O'Connor KC, Appel H, Bregoli L, Call ME, Catz I, Chan JA, Moore NH, Warren KG, Wong SJ, Hafler DA, Wucherpfennig KW. Antibodies from inflamed central nervous system tissue recognize myelin oligodendrocyte glycoprotein. J Immunol 2005; 175:1974-82. PubMed
  • Call ME, Wucherpfennig KW. THE T CELL RECEPTOR: Critical Role of the Membrane Environment in Receptor Assembly and Function. Annu Rev Immunol 2005; 23:101-25. 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
  • Maecker B, Sherr DH, Vonderheide RH, von Bergwelt-Baildon MS, Hirano N, Anderson KS, Xia Z, Butler MO, Wucherpfennig KW, O'Hara C, Cole G, Kwak SS, Ramstedt U, Tomlinson AJ, Chicz RM, Nadler LM, Schultze JL. The shared tumor-associated antigen cytochrome P450 1B1 is recognized by specific cytotoxic T cells. Blood 2003; 102:3287-94. PubMed
  • Reddy J, Bettelli E, Nicholson L, Waldner H, Jang MH, Wucherpfennig KW, Kuchroo VK. Detection of autoreactive myelin proteolipid protein 139-151-specific T cells by using MHC II (IAs) tetramers. J Immunol 2003; 170:870-7. PubMed
  • Belmares MP, Busch R, Wucherpfennig KW, McConnell HM, Mellins ED. Structural factors contributing to DM susceptibility of MHC class II/peptide complexes. J Immunol 2002; 169:5109-17. PubMed
  • von Bergwelt-Baildon MS, Vonderheide RH, Maecker B, Hirano N, Anderson KS, Butler MO, Xia Z, Zeng WY, Wucherpfennig KW, Nadler LM, Schultze JL. Human primary and memory cytotoxic T lymphocyte responses are efficiently induced by means of CD40-activated B cells as antigen-presenting cells: potential for clinical application. Blood 2002; 99:3319-25. PubMed
  • Vonderheide RH, Schultze JL, Anderson KS, Maecker B, Butler MO, Xia Z, Kuroda MJ, von Bergwelt-Baildon MS, Bedor MM, Hoar KM, Schnipper DR, Brooks MW, Letvin NL, Stephans KF, Wucherpfennig KW, Hahn WC, Nadler LM. Equivalent induction of telomerase-specific cytotoxic T lymphocytes from tumor-bearing patients and healthy individuals. Cancer Res 2001; 61:8366-70. PubMed
  • Wucherpfennig KW. Mechanisms for the induction of autoimmunity by infectious agents. J Clin Invest 2001; 108:1097-104. PubMed
  • Bourcier KD, Lim DG, Ding YH, Smith KJ, Wucherpfennig K, Hafler DA. Conserved CDR3 regions in T-cell receptor (TCR) CD8(+) T cells that recognize the Tax11-19/HLA-A*0201 complex in a subject infected with human T-cell leukemia virus type 1: relationship of T-cell fine specificity and major histocompatibility complex/pepti J Virol 2001; 75:9836-43. PubMed
  • Panoutsakopoulou V, Sanchirico ME, Huster KM, Jansson M, Granucci F, Shim DJ, Wucherpfennig KW, Cantor H. Analysis of the relationship between viral infection and autoimmune disease. Immunity 2001; 15:137-47. PubMed
  • Lee KH, Wucherpfennig KW, Wiley DC. Structure of a human insulin peptide-HLA-DQ8 complex and susceptibility to type 1 diabetes. Nat Immunol 2001; 2:501-7. PubMed
  • Wucherpfennig KW. Structural basis of molecular mimicry. J Autoimmun 2001; 16:293-302. PubMed
  • Appel H, Seth NP, Gauthier L, Wucherpfennig KW. Anergy induction by dimeric TCR ligands. J Immunol 2001; 166:5279-85. PubMed
  • Malherbe L, Filippi C, Julia V, Foucras G, Moro M, Appel H, Wucherpfennig K, Gu. Selective activation and expansion of high-affinity CD4+ T cells in resistant mice upon infection with Leishmania major. Immunity 2001; 13:771-82. PubMed
  • Yu B, Gauthier L, Hausmann DH, Wucherpfennig KW. Binding of conserved islet peptides by human and murine MHC class II molecules associated with susceptibility to type I diabetes. Eur J Immunol 2000; 30:2497-506. PubMed
  • Krogsgaard M, Wucherpfennig KW, Cannella B, Hansen BE, Svejgaard A, Pyrdol J, Ditzel H, Raine C, Engberg J, Fugger L, Canella B. Visualization of myelin basic protein (MBP) T cell epitopes in multiple sclerosis lesions using a monoclonal antibody specific for the human histocompatibility leukocyte antigen (HLA)-DR2-MBP 85-99 complex. J Exp Med 2000; 191:1395-412. PubMed
  • Appel H, Gauthier L, Pyrdol J, Wucherpfennig KW. Kinetics of T-cell receptor binding by bivalent HLA-DR.Peptide complexes that activate antigen-specific human T-cells. J Biol Chem 2000; 275:312-21. 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.
  • Hausmann DH, Yu B, Hausmann S, Wucherpfennig KW. pH-dependent peptide binding properties of the type I diabetes-associated I-Ag7 molecule: rapid release of CLIP at an endosomal pH. J Exp Med 1999; 189:1723-34. PubMed
  • Hausmann S, Biddison WE, Smith KJ, Ding YH, Garboczi DN, Utz U, Wiley DC, Wucherpfennig KW. Peptide recognition by two HLA-A2/Tax11-19-specific T cell clones in relationship to their MHC/peptide/TCR crystal structures. J Immunol 1999; 162:5389-97. PubMed
  • Fridkis-Hareli M, Neveu JM, Robinson RA, Lane WS, Gauthier L, Wucherpfennig KW, Sela M, Strominger JL. Binding motifs of copolymer 1 to multiple sclerosis- and rheumatoid arthritis-associated HLA-DR molecules. J Immunol 1999; 162:4697-704. PubMed
  • Hausmann S, Martin M, Gauthier L, Wucherpfennig KW. Structural features of autoreactive TCR that determine the degree of degeneracy in peptide recognition. J Immunol 1999; 162:338-44. PubMed
  • Smith KJ, Pyrdol J, Gauthier L, Wiley DC, Wucherpfennig KW. Crystal structure of HLA-DR2 (DRA*0101, DRB1*1501) complexed with a peptide from human myelin basic protein. J Exp Med 1998; 188:1511-20. PubMed
  • Gauthier L, Smith KJ, Pyrdol J, Kalandadze A, Strominger JL, Wiley DC, Wucherpfennig KW. Expression and crystallization of the complex of HLA-DR2 (DRA, DRB1*1501) and an immunodominant peptide of human myelin basic protein. Proc Natl Acad Sci U S A 1998; 95:11828-33. PubMed
  • Eble JA, Wucherpfennig KW, Gauthier L, Dersch P, Krukonis E, Isberg RR, Hemler ME. Recombinant soluble human alpha 3 beta 1 integrin: purification, processing, regulation, and specific binding to laminin-5 and invasin in a mutually exclusive manner. Biochemistry 1998; 37:10945-55. PubMed
  • Liedtke W, Cannella B, Mazzaccaro RJ, Clements JM, Miller KM, Wucherpfennig KW, Gearing AJ, Raine CS. Effective treatment of models of multiple sclerosis by matrix metalloproteinase inhibitors. Ann Neurol 1998; 44:35-46. PubMed
  • Hausmann S, Wucherpfennig KW. Activation of autoreactive T cells by peptides from human pathogens. Curr Opin Immunol 1998; 9:831-8. PubMed
  • Warren KG, Catz I, Wucherpfennig KW. Tolerance induction to myelin basic protein by intravenous synthetic peptides containing epitope P85 VVHFFKNIVTP96 in chronic progressive multiple sclerosis. J Neurol Sci 1997; 152:31-8. PubMed
  • Wucherpfennig KW, Catz I, Hausmann S, Strominger JL, Steinman L, Warren KG. Recognition of the immunodominant myelin basic protein peptide by autoantibodies and HLA-DR2-restricted T cell clones from multiple sclerosis patients. Identity of key contact residues in the B-cell and T-cell epitopes. J Clin Invest 1997; 100:1114-22. PubMed
  • Kalandadze A, Galleno M, Foncerrada L, Strominger JL, Wucherpfennig KW. Expression of recombinant HLA-DR2 molecules. Replacement of the hydrophobic transmembrane region by a leucine zipper dimerization motif allows the assembly and secretion of soluble DR alpha beta heterodimers. J Biol Chem 1996; 271:20156-62. PubMed
  • Wucherpfennig KW, Hafler DA, Strominger JL. Structure of human T-cell receptors specific for an immunodominant myelin basic protein peptide: positioning of T-cell receptors on HLA-DR2/peptide complexes. Proc Natl Acad Sci U S A 1995; 92:8896-900. PubMed
  • Wucherpfennig KW, Strominger JL. Selective binding of self peptides to disease-associated major histocompatibility complex (MHC) molecules: a mechanism for MHC-linked susceptibility to human autoimmune diseases. J Exp Med 1995; 181:1597-601. PubMed
  • Wucherpfennig KW, Strominger JL. Molecular mimicry in T cell-mediated autoimmunity: viral peptides activate human T cell clones specific for myelin basic protein. Cell 1995; 80:695-705. PubMed
  • Chung S, Wucherpfennig KW, Friedman SM, Hafler DA, Strominger JL. Functional three-domain single-chain T-cell receptors. Proc Natl Acad Sci U S A 1994; 91:12654-8. PubMed
  • Wucherpfennig KW. Autoimmunity in the central nervous system: mechanisms of antigen presentation and recognition. Clin Immunol Immunopathol 1994; 72:293-306. PubMed
  • Wucherpfennig KW, Zhang J, Witek C, Matsui M, Modabber Y, Ota K, Hafler DA. Clonal expansion and persistence of human T cells specific for an immunodominant myelin basic protein peptide. J Immunol 1994; 152:5581-92. PubMed
  • Wucherpfennig KW, Sette A, Southwood S, Oseroff C, Matsui M, Strominger JL, Hafler DA. Structural requirements for binding of an immunodominant myelin basic protein peptide to DR2 isotypes and for its recognition by human T cell clones. J Exp Med 1994; 179:279-90. PubMed
  • Wucherpfennig KW, Liao YJ, Prendergast M, Prendergast J, Hafler DA, Strominger JL. Human fetal liver gamma/delta T cells predominantly use unusual rearrangements of the T cell receptor delta and gamma loci expressed on both CD4+CD8- and CD4-CD8- gamma/delta T cells. J Exp Med 1993; 177:425-32. PubMed
  • Wucherpfennig KW, Newcombe J, Li H, Keddy C, Cuzner ML, Hafler DA. Gamma delta T-cell receptor repertoire in acute multiple sclerosis lesions. Proc Natl Acad Sci U S A 1992; 89:4588-92. PubMed
  • H. Characterization of HTLV-I in vivo infected T cell clones. IL-2-independent growth of nontransformed T cells. J Immunol 1992; 148:3256-63. PubMed
  • Wucherpfennig KW, Newcombe J, Li H, Keddy C, Cuzner ML, Hafler DA. T cell receptor V alpha-V beta repertoire and cytokine gene expression in active multiple sclerosis lesions. J Exp Med 1992; 175:993-1002. PubMed
  • Wucherpfennig KW, H. T-cell activation by autologous human T-cell leukemia virus type I-infected T-cell clones. Proc Natl Acad Sci U S A 1992; 89:2110-4. PubMed
  • Balk SP, Ebert EC, Blumenthal RL, McDermott FV, Wucherpfennig KW, Landau SB, Blumberg RS. Oligoclonal expansion and CD1 recognition by human intestinal intraepithelial lymphocytes. Science 1991; 253:1411-5. PubMed
  • Wucherpfennig KW, Weiner HL, Hafler DA. T-cell recognition of myelin basic protein. Immunol Today 1991; 12:277-82. PubMed
  • Lee SJ, Wucherpfennig KW, Brod SA, Benjamin D, Weiner HL, Hafler DA. Common T-cell receptor V beta usage in oligoclonal T lymphocytes derived from cerebrospinal fluid and blood of patients with multiple sclerosis. Ann Neurol 1991; 29:33-40. PubMed
  • Wucherpfennig KW, Ota K, Endo N, Seidman JG, Rosenzweig A, Weiner HL, Hafler DA. Shared human T cell receptor V beta usage to immunodominant regions of myelin basic protein. Science 1990; 248:1016-9. PubMed
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