Project Grant F30CA317805

ROLE OF PERSISTENT T CELL RECEPTOR SIGNALING IN SHAPING CD8+ T CELL RESIDENCY, FATE, AND FUNCTION AGAINST SOLID TUMORS - PROJECT SUMMARY/ABSTRACT CYTOTOXIC CD8+ T CELLS ARE CRITICAL EFFECTORS IN FIGHTING AGAINST TUMORS. HOWEVER, AS CANCER PROGRESSES, MANY OF THESE CELLS ARE DRIVEN TOWARDS A STATE OF FUNCTIONAL EXHAUSTION THROUGH CHRONIC STIMULATION OF THEIR T CELL RECEPTOR (TCR) BY TUMOR ANTIGEN. MANY NOVEL IMMUNOTHERAPIES ATTEMPT TO MITIGATE OR REVERSE THIS DYSFUNCTIONAL CD8+ T CELL STATE THROUGH DIRECT TARGETING OF PATHWAYS BELIEVED TO DRIVE EXHAUSTION, YET THEIR EFFICACY REMAINS SUBOPTIMAL, PARTICULARLY IN SOLID TUMORS. CANCER REMAINS THE SECOND HIGHEST CAUSE OF DEATH NATIONALLY, AND IT IS CRUCIAL TO FURTHER INTERROGATE THE CD8+ T CELL RESPONSE TO CANCER. OF PARTICULAR NOTE, MUCH OF THE WORK TO DEFINE T CELL EXHAUSTION HAS HISTORICALLY COME FROM CHRONIC INFECTION MODELS, WITH THE FINDINGS BROADLY APPLIED TO CANCER SETTINGS DUE TO THE SHARED PRESENCE OF CHRONIC ANTIGEN WITHIN EACH DISEASE STATE. HOWEVER, TUMORS OPERATE QUITE DIFFERENTLY FROM THESE INFECTION MODELS WITH A LOCALIZED DEPOSITION OF ANTIGEN, A PROPENSITY TO DOWNREGULATE ANTIGEN PRESENTATION, AND, IN SOME CASES, POTENTIAL FOR SURGICAL RESECTION. THESE DIFFERENCES CAN ALL AFFECT THE DURATION AND PERSISTENCE OF TCR SIGNALING IN CD8+ T CELLS SENSING CANCER ANTIGEN. IT REMAINS UNKNOWN HOW THIS MAINTENANCE AND LOSS OF ANTIGEN SENSING SHAPES THE PHENOTYPE, FUNCTION, AND RESIDENCY OF CD8+ T CELLS. FURTHERMORE, IT REMAINS UNCLEAR IF THIS LOCALIZED SOURCE OF ANTIGEN WITHIN A SOLID TUMOR IMPACTS ANTI-TUMOR T CELLS IN DISTANT NON-TUMOR TISSUES, WHICH PLAY A LARGE ROLE IN PROTECTION AGAINST METASTASES. IN THIS PROPOSAL, THE TRAINEE WILL ADDRESS THESE GAPS IN UNDERSTANDINGS OF CD8+ T CELL ANTI-TUMOR IMMUNITY. TO THIS END, THE TRAINEE'S LAB GENERATED A TUMOR-SPECIFIC T CELL MODEL THAT ALLOWS FOR INDUCIBLE, SELECTIVE EXCISION OF THE TCR GENE LOCUS, WHICH WILL BE TRANSFERRED INTO MICE THAT DEVELOP AUTOCHTHONOUS LUNG TUMORS LASTING FOR 20+ WEEKS. THIS APPROACH STANDS OUT DUE TO THE LONGEVITY OF TUMOR GROWTH, WHICH HAS BEEN A PRIOR LIMITING FACTOR IN STUDIES ON T CELL EXHAUSTION WITHIN CANCER, AND THE PRECISION WITH WHICH THE TRAINEE IS ABLE TO INTERROGATE THE ROLE OF PERSISTENT VERSUS LOST TCR SIGNALING. AIM 1 WILL DETERMINE HOW PERSISTENT AND LOST ANTIGEN SIGNALING AFFECTS ANTI-TUMOR T CELL PHENOTYPE, FUNCTION, AND LOCALIZATION WITHIN THE TUMOR MICROENVIRONMENT, POTENTIALLY DEMONSTRATING INCREASED PLASTICITY OR RIGIDITY OF TUMOR-RESPONSIVE T CELLS IN THEIR FATE ACROSS TUMOR DEVELOPMENT. AIM 2 WILL EXPAND OUTSIDE THE TUMOR MICROENVIRONMENT TO DETERMINE TEMPORAL AND THERAPEUTIC EFFECTS ON TUMOR-SPECIFIC T CELLS DISPERSAL TO NON-TUMOR SITES, INCLUDING INVESTIGATING IF CELLS ARE RELIANT ON MAINTAINED TCR SIGNALING FOR RESIDENCY WITHIN THE TUMOR OR NON-TUMOR TISSUES. NOT ONLY WILL THIS WORK SHED IMPORTANT INSIGHT ON BASIC IMMUNOLOGIC PRINCIPLES, BUT IT WILL ALSO RELAY INFORMATION ABOUT HOW TCR SIGNALING MAY BE MANIPULATED FOR THERAPEUTIC USE AND IMPROVED ANTI-TUMOR IMMUNITY. THIS PROPOSAL WILL BE COMPLETED AT THE UNIVERSITY OF MINNESOTA IN THE LABORATORY OF DAVID MASOPUST, PH.D., A WORLD-LEADER IN THE STUDY OF MEMORY T CELL FUNCTION AND IMMUNOSURVEILLANCE. THROUGH THIS RESEARCH AND COMPLEMENTING TRAINING ACTIVITIES, THIS PROPOSAL IS POISED FOR GREAT SUCCESS AS A TRAINEE-CENTERED FELLOWSHIP.