Thomas Gajewski, M.D., Ph.D.

Research Summary

Regulation of T-cell Activation, T-cell Signaling, Tumor Immunology, Immunotherapy of Melanoma

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 Lymphocyte Biology

Naive T cells that have never seen antigen lack effector function and must acquire such functions through a differentiation process. Initial activation depends on engagement of the T cell receptor (TCR) as well as additional receptor/ligation interactions that influence the quantity and quality of the T cell response. Positive regulatory influences include CD28 engagement by B7, and negative regulatory processes include ligation of CTLA4 or by induction of an unresponsive state termed anergy. In addition to this quantitative level of control, T cell activation is also qualitatively influenced by exogenous cytokines that promote differentiation down distinct lineages of effector cell phenotype having specialized functions. We study the molecular and biochemical events that mediate regulation of T cells in the naive, effector, and anergic states, as well as the process of transitioning from one state to another. These experiments rely upon mutagenesis and viral transduction techniques, transgenic and knockout mice, and a variety of cellular immunology approaches.

Regulation of 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. We hypothesize that part of the defect may be due to inappropriate T cell differentiation or the dominant effects of negative regulatory influences on T cell activation. In order to determine the factors necessary for tumor rejection when it successfully occurs, we study the rejection of immunogenic tumors in knockout mice lacking individual molecules expected to affect specific aspects of T cell activation and differentiation. To examine which factors are sufficient to induce anti-tumor immunity, we supply these factors in antigen-specific vaccination strategies to promote rejection of established tumors in mice. Successful preclinical tumor vaccine results are then applied to clinical trials in the melanoma clinic which I also direct. Other immunologic manipulations are explored in our clinical cancer immunotherapy group.