Project 1: Understanding how somatic mutations incite T cell cancers
Signal transducer and activator of transcription 3 (STAT3) is a vital transcription factor that mediates key pro- and anti-inflammatory functions in immune cells. STAT3 promotes T cell proliferation, survival and differentiation of pro-inflammatory T effector cell subsets. The importance of STAT3 is further illustrated by the fact that germline mutations result in severe developmental defects and autoimmunity. STAT3 hyperactivity is observed in a variety of solid and blood cancers where it is known to drive cancer ‘hallmark’ processes including metastasis, angiogenesis, and insensitivity to anti-growth signals. Somatic mutations in STAT3 are commonly associated with hematologic cancers, primarily T cell leukemias. Our lab seeks to determine how these affect STAT3 function and thereby drive oncogenesis.

Project 2: Understanding how cancers subvert anti-tumor T cell responses
T cells are central mediators of both immunity and immuno-pathology. Thus, the immune system seeks to establish tolerance, a balanced state whereby T cell responses against legitimate challenges are robust, yet properly tempered while those against self or innocuous stimuli are prohibited. Too much tolerance can also be a problem; pathogens and cancers often co-opt tolerogenic mechanisms to suppress inflammation. For instance, chronic exposure to tumor-derived antigens and inhibitory molecules can drive T cells to dysfunctional states that, at best, do not provide protection and, at worst, conspire against it. Our lab seeks to identify cellular, molecular and epigenetic processes that mediate T cell dysfunction within the tumor microenvironment and thereby inform development and/or implementation of T cell ‘reinvigoration’ strategies for metastatic disease. A key focus of this work is to understand how cytokine signaling via the JAK-STAT pathway drives both beneficial anti-tumor and deleterious pro-tumor T cell responses.