Project Grant DP2AI176139

DISSECTING THE ENHANCER LOGIC GOVERNING IMMUNE CELL FATE DECISIONS - PROJECT SUMMARY CD8 T CELLS ARE A CRITICAL COMPONENT OF AN EFFECTIVE ANTI-TUMOR RESPONSE. THEREFORE, A MAJOR GOAL IN CANCER IMMUNOLOGY, AND MORE BROADLY IN IMMUNOBIOLOGY, HAS BEEN TO UNDERSTAND HOW SPECIFIC DISEASE CONTEXTS GOVERN T CELL FATE AND FUNCTION. A GROWING AND LARGELY DESCRIPTIVE ATLAS OF CHROMATIN ACCESSIBILITY HAS BEGUN PROVIDING RICH INSIGHT INTO THE EPIGENETIC LANDSCAPE OF CD8 T CELLS, YET IT REMAINS A CHALLENGE TO UNDERSTAND CAUSE-AND-EFFECT RELATIONSHIPS FROM SUCH DATA. FURTHERMORE, T CELL FATE SPECIFICATION, LIKE MANY CELLULAR DIFFERENTIATION PROCESSES, DEVELOPS WITH A CONTINUUM OF PHENOTYPIC AND FUNCTIONAL INTERMEDIATE STATES. THIS PROMPTS THE QUESTION, WHICH EPIGENETIC MECHANISMS ARE CAUSAL IN DRIVING STATE TRANSITIONS WITHIN CD8 T CELLS? WHAT ARE THE EARLIEST SIGNALING PATHWAYS THAT DRIVE COMMITMENT TO PARTICULAR T CELL PHENOTYPE? HOW DOES TISSUE CONTEXT SHAPE ANTI-TUMOR T CELL IMMUNITY? OUR PROPOSAL ADDRESSES THESE QUESTIONS BY LEVERAGING LOSS- OF-FUNCTION (LOF) AND GAIN-OF-FUNCTION (GOF) APPROACHES FOR ENHANCER EDITING TO IDENTIFY HOW, WHEN AND WHERE CD8 T CELL FATE COMMITMENT HAPPENS IN VIVO. AS AN INITIAL APPLICATION, WE WILL USE THIS FRAMEWORK TO UNDERSTAND THE CONTEXT-SPECIFIC EPIGENETIC MECHANISMS GOVERNING EXHAUSTED CD8 T CELL DIFFERENTIATION IN THE TUMOR MICROENVIRONMENT. WE FOCUS IN PARTICULAR ON COMPARING PROGENITOR EXHAUSTED T CELLS IN MELANOMA VS. HEPATOCELLULAR CARCINOMA SINCE THESE TWO DISEASES HAVE MARKEDLY DIFFERENT TISSUE-SPECIFIC SIGNALING, HAVE DIFFERENTIAL RESPONSIVITY TO IMMUNE CHECKPOINT BLOCKADE, AND MOST IMPORTANTLY, INDUCE BOTH SHARED AND TUMOR- SPECIFIC PATTERNS OF EPIGENETIC CHANGES. ALTHOUGH THIS PROJECT WILL YIELD FUNDAMENTAL INSIGHTS INTO T CELL REGULATION, WE ALSO AIM TO EXTEND EPIGENETIC REPROGRAMMING TO PRECLINICAL MODELS OF ADOPTIVE T CELL THERAPY WITH POTENTIAL THERAPEUTIC APPLICATION. THE NOVEL INTEGRATION OF TECHNOLOGIES TO ACHIEVE THESE GOALS PROMISES TO BE USEFUL FOR DIVERSE DISEASE CONTEXTS WHERE CD8 T CELLS PLAY A ROLE, IN CANCER AND BEYOND.