Thomas Gajewski, MD, PhD

Our laboratory studies the molecular and cellular regulation of T lymphocyte activation and differentiation, and in turn applies this information to preclinical and clinical efforts to promote anti-tumor immunity in vivo.

T cell activation. Because of its presumed central role in T cell regulation, our laboratory has been studying in greater detail the regulation of Ras pathway signaling. Using T cells from CAR Tg mice that are tansducible with adenoviral vectors, we have recently shown that T cell anergy can be reversed by active Ras. Using gene expression profiling and confirmatory experiments, we have identified diacylglycerol kinase–α as a key negative regulator of Ras activation and T cell function in the anergic state. Confocal microscopy approaches have revealed that the Ras activator RasGRP1 is recruited to the T cell/APC interface upon full activation. Much of our work is focused on the yin/yang between RasGRP1 and DGK-α in T cell activation, T cell differentiation, CD28 costimulation, and anergy.

Anti-tumor immunity. Recent work has suggested that most tumors express antigens that can be recognized as foreign by specific T cells. How and why tumors than grow and escape immune destruction has become a central problem in cancer biology. Potent vaccine strategies can prime and expand tumor antigen-specific T cells of the desired phenotype in vivo. However, downstream resistance mechanisms still often dominate. We have been exploring T cell anergy, suppression by CD4+CD25+ Tregs, engagement of inhibitory receptors such as PD-1 and CTLA-4, metabolic dysregulation, and insufficient T cell trafficking as mechanisms of tumor escape from immune attack. Concepts are explored both in mouse preclinical models and in human clinical trials in cancer patients.