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

Photo of Kai W. Wucherpfennig, MD, PhD

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


kai_wucherpfennig@dfci.harvard.edu

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Kai W. Wucherpfennig, MD, PhD

Dana-Farber Cancer Institute

EDUCATIONAL TITLES

  • Professor, Microbiology and Immunobiology, Harvard Medical School
  • Chair, Cancer Immunology and Virology, 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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  • Kula T, Dezfulian MH, Wang CI, Abdelfattah NS, Hartman ZC, Wucherpfennig KW, Lyerly HK, Elledge SJ. T-Scan: A Genome-wide Method for the Systematic Discovery of T Cell Epitopes. Cell 2019; 178:1016-1028.e13. PubMed
  • Janiszewska M, Tabassum DP, Castaño Z, Cristea S, Yamamoto KN, Kingston NL, Murphy KC, Shu S, Harper NW, Del Alcazar CG, Alečković M, Ekram MB, Cohen O, Kwak M, Qin Y, Laszewski T, Luoma A, Marusyk A, Wucherpfennig KW, Wagle N, Fan R, Michor F, McAllister SS, Polyak K. Subclonal cooperation drives metastasis by modulating local and systemic immune microenvironments. Nat Cell Biol 2019; 21:879-888. PubMed
  • Chan LL, Wucherpfennig KW, de Andrade LF. Visualization and quantification of NK cell-mediated cytotoxicity over extended time periods by image cytometry. J Immunol Methods 2019. PubMed
  • Hu X, Zhang J, Wang J, Fu J, Li T, Zheng X, Wang B, Gu S, Jiang P, Fan J, Ying X, Zhang J, Carroll MC, Wucherpfennig KW, Hacohen N, Zhang F, Zhang P, Liu JS, Li B, Liu XS. Landscape of B cell immunity and related immune evasion in human cancers. Nat Genet 2019; 51:560-567. PubMed
  • Grootjans J, Krupka N, Hosomi S, Matute JD, Hanley T, Saveljeva S, Gensollen T, Heijmans J, Li H, Limenitakis JP, Ganal-Vonarburg SC, Suo S, Luoma AM, Shimodaira Y, Duan J, Shih DQ, Conner ME, Glickman JN, Fuhler GM, Palm NW, de Zoete MR, van der Woude CJ, Yuan GC, Wucherpfennig KW, Targan SR, Rosenstiel P, Flavell RA, McCoy KD, Macpherson AJ, Kaser A, Blumberg RS. Epithelial endoplasmic reticulum stress orchestrates a protective IgA response. Science 2019; 363:993-998. PubMed
  • Keskin DB, Anandappa AJ, Sun J, Tirosh I, Mathewson ND, Li S, Oliveira G, Giobbie-Hurder A, Felt K, Gjini E, Shukla SA, Hu Z, Li L, Le PM, Allesøe RL, Richman AR, Kowalczyk MS, Abdelrahman S, Geduldig JE, Charbonneau S, Pelton K, Iorgulescu JB, Elagina L, Zhang W, Olive O, McCluskey C, Olsen LR, Stevens J, Lane WJ, Salazar AM, Daley H, Wen PY, Chiocca EA, Harden M, Lennon NJ, Gabriel S, Getz G, Lander ES, Regev A, Ritz J, Neuberg D, Rodig SJ, Ligon KL, Suvà ML, Wucherpfennig KW, Hacohen N, Fritsch EF, Livak KJ, Ott PA, Wu CJ, Reardon DA. Neoantigen vaccine generates intratumoral T cell responses in phase Ib glioblastoma trial. Nature 2018. PubMed
  • Formenti SC, Rudqvist NP, Golden E, Cooper B, Wennerberg E, Lhuillier C, Vanpouille-Box C, Friedman K, Ferrari de Andrade L, Wucherpfennig KW, Heguy A, Imai N, Gnjatic S, Emerson RO, Zhou XK, Zhang T, Chachoua A, Demaria S. Radiotherapy induces responses of lung cancer to CTLA-4 blockade. Nat Med 2018; 24:1845-1851. PubMed
  • Jiang P, Gu S, Pan D, Fu J, Sahu A, Hu X, Li Z, Traugh N, Bu X, Li B, Liu J, Freeman GJ, Brown MA, Wucherpfennig KW, Liu XS. Signatures of T cell dysfunction and exclusion predict cancer immunotherapy response. Nat Med 2018; 24:1550-1558. PubMed
  • Ito Y, Ashenberg O, Pyrdol J, Luoma AM, Rozenblatt-Rosen O, Hofree M, Christian E, Ferrari de Andrade L, Tay RE, Teyton L, Regev A, Dougan SK, Wucherpfennig KW. Rapid CLIP dissociation from MHC II promotes an unusual antigen presentation pathway in autoimmunity. J Exp Med 2018; 215:2617-2635. PubMed
  • Cremasco V, Astarita JL, Grauel AL, Keerthivasan S, MacIsaac KD, Woodruff MC, Wu M, Spel L, Santoro S, Amoozgar Z, Laszewski T, Cruz-Migoni S, Knoblich K, Fletcher AL, LaFleur M, Wucherpfennig KW, Pure E, Dranoff G, Carroll M, Turley SJ. FAP delineates heterogeneous and functionally divergent stromal cells in immune-excluded breast tumors. Cancer Immunol Res 2018. PubMed
  • Li AW, Sobral MC, Badrinath S, Choi Y, Graveline A, Stafford AG, Weaver JC, Dellacherie MO, Shih TY, Ali OA, Kim J, Wucherpfennig KW, Mooney DJ. A facile approach to enhance antigen response for personalized cancer vaccination. Nat Mater 2018. PubMed
  • Pan D, Kobayashi A, Jiang P, Ferrari de Andrade L, Tay RE, Luoma A, Tsoucas D, Qiu X, Lim K, Rao P, Long HW, Yuan GC, Doench J, Brown M, Liu S, Wucherpfennig KW. A major chromatin regulator determines resistance of tumor cells to T cell-mediated killing. Science 2018. PubMed
  • Ferrari de Andrade L, Tay RE, Pan D, Luoma AM, Ito Y, Badrinath S, Tsoucas D, Franz B, May KF, Harvey CJ, Kobold S, Pyrdol JW, Yoon C, Yuan GC, Hodi FS, Dranoff G, Wucherpfennig KW. Antibody-mediated inhibition of MICA and MICB shedding promotes NK cell-driven tumor immunity. Science 2018; 359:1537-1542. PubMed
  • Schmid D, Park CG, Hartl CA, Subedi N, Cartwright AN, Puerto RB, Zheng Y, Maiarana J, Freeman GJ, Wucherpfennig KW, Irvine DJ, Goldberg MS. T cell-targeting nanoparticles focus delivery of immunotherapy to improve antitumor immunity. Nat Commun 2017; 8:1747. PubMed
  • Reardon DA, Wucherpfennig K, Chiocca EA. Immunotherapy for glioblastoma: on the sidelines or in the game? Discov Med 2017; 24:201-208. PubMed
  • Ott PA, Hu Z, Keskin DB, Shukla SA, Sun J, Bozym DJ, Zhang W, Luoma A, Giobbie-Hurder A, Peter L, Chen C, Olive O, Carter TA, Li S, Lieb DJ, Eisenhaure T, Gjini E, Stevens J, Lane WJ, Javeri I, Nellaiappan K, Salazar AM, Daley H, Seaman M, Buchbinder EI, Yoon CH, Harden M, Lennon N, Gabriel S, Rodig SJ, Barouch DH, Aster JC, Getz G, Wucherpfennig K, Neuberg D, Ritz J, Lander ES, Fritsch EF, Hacohen N, Wu CJ. An immunogenic personal neoantigen vaccine for patients with melanoma. Nature 2017. PubMed
  • Moffett HF, Cartwright ANR, Kim HJ, Godec J, Pyrdol J, Äijö T, Martinez GJ, Rao A, Lu J, Golub TR, Cantor H, Sharpe AH, Novina CD, Wucherpfennig KW. The microRNA miR-31 inhibits CD8(+) T cell function in chronic viral infection. Nat Immunol 2017; 18:791-799. PubMed
  • Reardon DA, Wen PY, Wucherpfennig KW, Sampson JH. Immunomodulation for glioblastoma. Curr Opin Neurol 2017. PubMed
  • Verbeke CS, Gordo S, Schubert DA, Lewin SA, Desai RM, Dobbins J, Wucherpfennig KW, Mooney DJ. Multicomponent Injectable Hydrogels for Antigen-Specific Tolerogenic Immune Modulation. Adv Healthc Mater 2017. PubMed
  • Gagnon E, Connolly A, Dobbins J, Wucherpfennig KW. Studying Dynamic Plasma Membrane Binding of TCR-CD3 Chains During Immunological Synapse Formation Using Donor-Quenching FRET and FLIM-FRET. Methods Mol Biol 2017; 1584:259-289. PubMed
  • Awad MM, Jones RE, Liu H, Lizotte PH, Ivanova EV, Kulkarni M, Herter-Sprie GS, Liao X, Santos AA, Bittinger MA, Keogh L, Koyama S, Almonte C, English JM, Barlow J, Richards WG, Barbie DA, Bass AJ, Rodig SJ, Hodi FS, Wucherpfennig KW, Jänne PA, Sholl LM, Hammerman PS, Wong KK, Bueno R. Cytotoxic T Cells in PD-L1-Positive Malignant Pleural Mesotheliomas Are Counterbalanced by Distinct Immunosuppressive Factors. Cancer Immunol Res 2016; 4:1038-1048. PubMed
  • Wucherpfennig KW, Cartwright AN. Genetic screens to study the immune system in cancer. Curr Opin Immunol 2016; 41:55-61. PubMed
  • Dobbins J, Gagnon E, Godec J, Pyrdol J, Vignali DA, Sharpe AH, Wucherpfennig KW. Binding of the cytoplasmic domain of CD28 to the plasma membrane inhibits Lck recruitment and signaling. Sci Signal 2016; 9:ra75. PubMed
  • Zhang C, Li X, Adelmant G, Dobbins J, Geisen C, Oser MG, Wucherpfenning KW, Marto JA, Kaelin WG. Peptidic degron in EID1 is recognized by an SCF E3 ligase complex containing the orphan F-box protein FBXO21. Proc Natl Acad Sci U S A 2015; 112:15372-15377. 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
  • 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; 16:1441-58. 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
  • 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 CD3ε 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 α-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.
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DF/HCC members that share similar concepts* with Kai W. Wucherpfennig, MD, PhD but have yet to coauthor a publication with this researcher.

* Concepts are MeSH terms, automatically derived from member publications

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