We use clinically relevant genetic cancer mouse models to understand how T cells become dysfunctional in solid tumors and how such T cells can be re-programmed for cancer immunotherapy. In particular, we investigate the molecular and epigenetic regulatory mechanisms underlying the induction, establishment and maintenance of functional unresponsiveness in oncogenic driver antigen-specific, and self/tumor antigen-specific T cells.
Cancer cells express mutated proteins that are distinct from the proteins in non-cancerous, normal cells, known as “tumor-specific antigens.” Over a century ago, scientists reasoned that our immune system (T cells) should be able to recognize these mutated proteins as “foreign” and eliminate cancer cells. However, though tumor-specific T cells are found within human tumors, tumor-specific T cells are not functional and allow cancers to grow unimpeded. The goal of our lab is to understand when, why and how such tumor-specific T cells become unresponsive to the tumor. We develop genetic cancer mouse models that mimic cancer development in patients, investigate tumor-specific T cell responses over the course of tumor development and define the mechanisms that are responsible for the failure to control and eliminate tumors. Based on the findings from our mouse models, together with our clinical colleagues we then work to define the “dysfunctional code” in human tumor-specific T cells and develop strategies for effective human cancer therapy.
T cell tolerance to self antigens is a state of functional unresponsiveness required to prevent autoimmunity. Many tumor antigens, however, are self-antigens and a critical challenge in tumor immunology is to develop strategies that break T cell tolerance to such self/tumor antigens without causing unacceptable autoimmune injury. We are using genetic mouse models of self-tolerance to define the T cell-intrinsic molecular and epigenetic programs that mediate the functional unresponsiveness to “self”, and design strategies to reprogram self-tolerant T cells for cancer immunotherapy through immunomodulatory interventions and innovative genome editing approaches.