Kai W. Wucherpfennig


Dana Farber Cancer Institute
Cancer Immunology, Dana Bldg., Rm.1410
44 Binney Street
Boston, MA 02115
Tel: 617-632-3086
Fax: 617-632-2662
Email: kai_wucherpfennig@dfci.harvard.edu
Visit my lab page here.




Recent work has shown that T cells play a central role in the natural history of cancers: tumor infiltration by CD8 T cells is a stronger predictor of patient survival than the anatomical spread of a cancer. Furthermore, recent clinical trials have shown that targeting of inhibitory receptors on the surface of T cells (CTLA-4, PD-1) induces durable responses in a subset of patients, despite the presence of metastatic disease. These studies unequivocally prove that modulation of T cell function is an important approach for the treatment of cancer. CD8 T cells are inhibited in tumor microenvironments by multiple regulatory cell populations, including tumor-associated macrophages, certain myeloid cell populations and regulatory T cells. We are addressing an important question that is largely unresolved: how do T cells integrate different negative signals and which intracellular molecules act as the critical switches in the control of T cell activity? 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 large set of genes that control T cell function in the tumor microenvironment. We are now deciphering the molecular function of these genes in anti-microbial immune responses. Also, we are actively working to exploit these new insights for the development of new cancer immunotherapies.

References:

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.



Last Update: 1/6/2014