BBS Faculty Member - Kai Wucherpfennig

Kai Wucherpfennig

Department of Cancer Immunology and AIDS

Dana Farber Cancer Institute
44 Binney St.
Smith Building, Room S736
Boston, MA 02115
Tel: 617-632-3086
Fax: 617-632-2662
Email: kai_wucherpfennig@dfci.harvard.edu
Lab Members: 10 postdoctoral fellows, 1 graduate student, 1 staff scientist
Visit my lab page here.



T cells in anti-tumor immunity

Clinical studies have shown that the number and activation state of tumor-infiltrating T cells can predict survival with a greater accuracy than anatomical staging methods. However, T cells are frequently inactivated in the tumor microenvironment. Recent clinical trials have shown that targeting of inhibitory receptors on T cells (PD-1 and CTLA-4) can induce durable responses in patients several different types of advanced cancer (including melanoma, renal and lung cancer). We are studying the molecular pathways responsible for inhibition of T cells in tumors, with the goal of reversing this functional block. We developed an
in vivo shRNA screening approach to identify shRNAs that can restore the functional activity of tumor-specific T cells. These studies are resulting in the identification of a substantial number of genes that control the function of T cells in tumors. We are studying the mechanisms by which these genes constrain T cell function, with the goal of developing novel approaches for improving anti-tumor T cell function.

Molecular mechanisms of T cell receptor recognition and signaling

We are also studying how antigens are presented to T cells and a T cell response is initiated. A particular interesting problem is how peptide antigens are selected for presentation by MHC molecules to T cells. We are defining the mechanisms by which HLA-DM, an enzyme that catalyzes peptide binding, shapes the selection of the peptide repertoire in the intracellular peptide loading compartment. We are also studying the mechanisms of T cell receptor recognition and initiation of signaling following antigen recognition using a variety of approaches.



Last Update: 6/24/2014



Publications

Zhou P, Shaffer DR, Alvarez Arias DA, Nakazaki Y, Pos W, Torres AJ, Cremasco V, Dougan S. K, 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: 52-57.
Pos W, Seth, D, 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: 1557-1568
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 2011; 12: 54-61.

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 CD3e cytoplasmic tyrosine-based motif. Cell 2008, 135:702-13.

Call ME, Schnell JR, Xu C, Lutz RA, Chou JJ, Wucherpfennig KW. The structure of the zeta-zeta transmembrane dimer reveals polar features essential for its assembly with the T cell receptor. Cell 2006; 127: 355-68.

Call ME, Pyrdol J, Wiedmann M, Wucherpfennig KW. The organizing principle in the formation of the T cell receptor-CD3 complex. Cell 2002; 111: 967-79.



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