Kai W. Wucherpfennig
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.
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