Immunology Faculty Member - Kai Wucherpfennig, MD, PhD

Kai Wucherpfennig, MD, PhD

Dana Farber Cancer Institute
Cancer Immunology, Smith 736
1 Jimmy Fund Way
Boston, MA 02215
Tel: 617-632-3086
Fax: 617-582-9164
Email: kai_wucherpfennig@dfci.harvard.edu
Visit my lab page here.



T cells play a central role as effector cells in cancer immunotherapy, as shown by the durable clinical responses to PD-1 and CTLA-4 antibodies in a subset of patients with advanced cancer. We are currently working on the following major topics: 1. Mechanisms of resistance to cancer immunotherapy. The majority of cancer patients still fail to benefit from cancer immunotherapy. We have established a substantial program that aims to identify the molecular mechanisms that allow tumor cells to resist T cell-mediated immune attack (Science 2018, 359: 770). We are working on a number of chromatin and transcriptional regulators expressed by cancer cells that are critical in this process in an effort to systematically define resistance mechanisms. Also, we are studying several gene products expressed by cancer cells as therapeutic targets. This effort aims to integrate mechanistic studies in mouse models with investigation of the microenvironment of human cancers. 2. Negative regulators of T cell and NK cell function in the tumor microenvironment. We have developed a novel in vivo approach to discover such inhibitory genes in the tumor microenvironment. These studies have resulted in the discovery of a substantial number of genes that control T cell function in the tumor microenvironment. We are now deciphering the molecular function of these genes in anti-tumor immunity. Also, we are actively working to exploit these new insights for the development of novel cancer immunotherapies (Science 2018, 359: 1537; Curr Opinion Immunology 2016, 41: 55; Nature 2014, 507: 118). 3. Mechanistic studies on immune cells in human cancers. It is critically important to define regulatory pathway directly in human cancers. We are using advanced technologies for in depth characterization of T cells and other immune cells in human cancers that are resistant to immunotherapy. This effort has already highlighted an exciting novel pathway for immunotherapy.



Last Update: 7/9/2018



Publications

1. Gagnon, E., Schubert, D. A., Gordo, S., Chu, H. H., and Wucherpfennig, K. W. (2012) Local changes in lipid environment of TCR microclusters regulate membrane binding by the CD3ε cytoplasmic domain, The Journal of Experimental Medicine 209, 2423-2439.

2. Schubert, D. A., Gordo, S., Sabatino, J. J., Jr., Vardhana, S., Gagnon, E., Sethi, D. K., Seth, N. P., Choudhuri, K., Reijonen, H., Nepom, G. T., Evavold, B. D., Dustin, M. L., and Wucherpfennig, K. W. (2012) Self-reactive human CD4 T cell clones form unusual immunological synapses, The Journal of Experimental Medicine 209, 335-352.

3. Pos, W., Sethi, D. K., Call, M. J., Schulze, M. S., Anders, A. K., Pyrdol, J., and Wucherpfennig, K. W. (2012) Crystal structure of the HLA-DM-HLA-DR1 complex defines mechanisms for rapid peptide selection, Cell 151, 1557-1568.

4. Anders, A. K., Call, M. J., Schulze, M. S., Fowler, K. D., Schubert, D. A., Seth, N. P., Sundberg, E. J., and Wucherpfennig, K. W. (2011) HLA-DM captures partially empty HLA-DR molecules for catalyzed removal of peptide, Nature Immunology 12, 54-61.

5. Xu, C., Gagnon, E., Call, M. E., Schnell, J. R., Schwieters, C. D., Carman, C. V., Chou, J. J., and Wucherpfennig, K. W. (2008) Regulation of T cell receptor activation by dynamic membrane binding of the CD3ε cytoplasmic tyrosine-based motif, Cell 135, 702-713.


Kim YC, Zhang AH, Yoon J, Culp WE, Lees JR, Wucherpfennig KW, Scott DW. Engineered MBP-specific human Tregs ameliorate MOG-induced EAE through IL-2-triggered inhibition of effector T cells. J Autoimmun. 2018 May 29. PMID: 29857928.

Clark LE, Mahmutovic S, Raymond DD, Dilanyan T, Koma T, Manning JT, Shankar S, Levis SC, Briggiler AM, Enria DA, Wucherpfennig KW, Paessler S, Abraham J. Vaccine-elicited receptor-binding site antibodies neutralize two New World hemorrhagic fever arenaviruses. Nat Commun. 2018 May 14; 9(1):1884. PMID: 29760382.

Filbin MG, Tirosh I, Hovestadt V, Shaw ML, Escalante LE, Mathewson ND, Neftel C, Frank N, Pelton K, Hebert CM, Haberler C, Yizhak K, Gojo J, Egervari K, Mount C, van Galen P, Bonal DM, Nguyen QD, Beck A, Sinai C, Czech T, Dorfer C, Goumnerova L, Lavarino C, Carcaboso AM, Mora J, Mylvaganam R, Luo CC, Peyrl A, Popovic M, Azizi A, Batchelor TT, Frosch MP, Martinez-Lage M, Kieran MW, Bandopadhayay P, Beroukhim R, Fritsch G, Getz G, Rozenblatt-Rosen O, Wucherpfennig KW, Louis DN, Monje M, Slavc I, Ligon KL, Golub TR, Regev A, Bernstein BE, Suvà ML. Developmental and oncogenic programs in H3K27M gliomas dissected by single-cell RNA-seq. Science. 2018 04 20; 360(6386):331-335. PMID: 29674595.

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 Mar 30; 359(6383):1537-1542. PMID: 29599246.

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. Corrigendum: An immunogenic personal neoantigen vaccine for patients with melanoma. Nature. 2018 Mar 14; 555(7696):402. PMID: 29542692.

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 Jun; 17(6):528-534. PMID: 29507416.

Choi IK, Wang Z, Ke Q, Hong M, Qian Y, Zhao X, Liu Y, Kim HJ, Ritz J, Cantor H, Rajewsky K, Wucherpfennig KW, Zhang B. Signaling by the Epstein-Barr virus LMP1 protein induces potent cytotoxic CD4+ and CD8+ T cell responses. Proc Natl Acad Sci U S A. 2018 Jan 23; 115(4):E686-E695. PMID: 29311309.

Pan D, Kobayashi A, Jiang P, Ferrari de Andrade L, Tay RE, Luoma AM, Tsoucas D, Qiu X, Lim K, Rao P, Long HW, Yuan GC, Doench J, Brown M, Liu XS, Wucherpfennig KW. A major chromatin regulator determines resistance of tumor cells to T cell-mediated killing. Science. 2018 02 16; 359(6377):770-775. PMID: 29301958.



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