Mary Philip, M.D., Ph.D.

Assistant Professor of Medicine, Division of Hematology/Oncology
Assistant Professor of Pathology, Microbiology and Immunology

A-3314 Medical Center North
1161 21st Avenue South
Nashville
Tennessee
37232
615.875.1872

Hematology, Cancer Immunology, T cells, Epigenetics, Autoimmunity, Differentiation

Research Description

The immune system has enormous power to detect and eliminate pathogens; however, CD8 T cells specific for (mutated) tumor antigens found within solid tumors are often dysfunctional, allowing tumors to progress. Hallmarks of tumor-specific T cell (TST) dysfunction in mice and humans include the expression of inhibitory receptors (e.g. PD1, CTLA4) and loss of effector function. The clinical success of immune checkpoint blockade and adoptive T cell therapy in some cancer patients demonstrates the potential of TST to mediate anti-tumor responses; however, important challenges and questions remain, including how to predict which patients will respond to therapy and how to design new immunotherapies for those patients who do not respond.
 
My research program utilizes clinically-relevant genetic cancer mouse models to understand the molecular and epigenetic regulatory mechanisms underlying TST dysfunction and design cutting-edge strategies to override TST dysfunction to improve cancer immunotherapy. Projects aim to (i) elucidate the mechanisms driving early TST dysfunction, (ii) determine how antigen chronicity drives dysfunction programming in TST, and (iii) design and test strategies, including epigenome editing, to reprogram dysfunctional TST for immunotherapy. We showed that even highly-functional memory T cells differentiate to a conserved dysfunctional chromatin state in tumors; thus, successful immunotherapy will require a multi-pronged strategy aimed at shifting dysfunctional TST out of the dysfunctional chromatin state and “bullet-proofing” these reprogrammed TST to prevent reversion to the dysfunctional state.

Publications on PubMed.gov