Project Grant F31CA306057

INVESTIGATING THE ANTI-TUMOR ROLES OF TUMOR-DRAINING LYMPH NODES IN RENAL CELL CARCINOMA - PROJECT SUMMARY/ABSTRACT WHILE CANCER IMMUNOTHERAPY HAS TRANSFORMED THE TREATMENT OF SOLID TUMORS, MOST PATIENTS DO NOT RECEIVE DURABLE CLINICAL BENEFIT. CD8+ T CELLS ARE CRITICAL MEDIATORS OF ANTI-TUMOR IMMUNITY, TARGETING AND KILLING CANCER CELLS, WITH IMMUNE CHECKPOINT BLOCKADE (ICB) THERAPIES DESIGNED TO AMPLIFY THEIR TUMOR-SPECIFIC CYTOTOXIC FUNCTIONS. UNDER CHRONIC ANTIGEN STIMULATION IN THE TUMOR MICROENVIRONMENT (TME), EXHAUSTED CD8+ T CELLS PROGRESSIVELY DIFFERENTIATE FROM PROGENITOR EXHAUSTED (TPEX) CELLS WITH SELF-RENEWAL CAPACITY, TO INTERMEDIATE EXHAUSTED (TEX-INT) CELLS WITH PEAK CYTOTOXICITY, AND FINALLY TO TERMINALLY EXHAUSTED (TTEX) CELLS WITH DIMINISHED PROLIFERATION AND EFFECTOR FUNCTIONS. IN MOUSE LUNG CANCER MODELS, THE TDLN WAS IDENTIFIED AS A RESERVOIR OF TPEX THAT DIFFERENTIATE INTO TUMOR- INFILTRATING LYMPHOCYTES (TILS), SUSTAINING ANTI-TUMOR IMMUNE RESPONSES OVER TIME. ADDITIONALLY, TPEX ARE THE PRIMARY TARGET OF ICB, EXPANDING AND DIFFERENTIATING INTO TEX-INT THAT MEDIATE EFFECTIVE ANTI-TUMOR IMMUNITY. HOWEVER, GIVEN THE LIMITED EFFICACY OF ICB IN MOST PATIENTS, IT REMAINS UNCLEAR WHETHER THESE FINDINGS ARE GENERALIZABLE ACROSS CANCER TYPES (OR ARE MODEL-SPECIFIC), AND WHETHER THIS BIOLOGY TRANSLATES TO HUMAN CANCERS. TO INVESTIGATE THIS, OUR LAB HAS EXTENSIVELY CHARACTERIZED TILS IN PATIENTS WITH CLEAR CELL RENAL CELL CARCINOMA (RCC) THROUGH SINGLE-CELL RNA SEQUENCING (SCRNA-SEQ), ESTABLISHING THAT TUMOR-SPECIFIC CD8+ T CELLS ARE OVERWHELMINGLY FOUND WITHIN EXHAUSTED T CELL COMPARTMENTS. FURTHER, SCRNA-SEQ OF HUMAN RCC TILS FOUND A HIGHER BASELINE OF TPEX AND A GREATER SHIFT FROM TPEX TO TTEX IN PATIENTS RESPONDING TO ANTI-PD-1-BASED ICB COMPARED TO NON-RESPONDERS, SUGGESTING TPEX ARE CRITICAL FOR ICB RESPONSE IN RCC. HOWEVER, THE TUMOR- SPECIFICITY, PHENOTYPIC STATES, TISSUE COMPARTMENTALIZATION, AND EFFECTOR FUNCTIONS OF CD8+ T CELLS IN SOLID TUMORS ARE NOT FULLY UNDERSTOOD. IN SPECIFIC AIM 1, I WILL LEVERAGE COLLABORATIONS WITH SURGEONS, PATHOLOGISTS, AND CLINICAL ONCOLOGISTS TO IDENTIFY TUMOR-SPECIFIC CD8+ T CELLS IN MATCHED TUMOR AND TDLN SPECIMENS FROM RCC PATIENTS, CHARACTERIZING THEIR LINEAGE RELATIONSHIP, PHENOTYPE, AND EFFECTOR FUNCTIONS. THIS WILL DEFINE THE ROLE OF THE PERIPHERY AND T CELL SUBSETS IN ANTI-TUMOR RESPONSES IN HUMAN SOLID TUMORS. IN SPECIFIC AIM 2, I WILL UTILIZE A DOMINANT ANTIGEN-ENGINEERED SYNGENEIC MOUSE MODEL OF RCC TO TRACK TDLN-DERIVED TUMOR-SPECIFIC CD8+ T CELL MIGRATION, INVESTIGATING WHETHER TDLN ANTI-TUMOR RESPONSES ARE CONSISTENT ACROSS IMMUNOTHERAPY-TREATED CANCERS AND PROVIDING CRITICAL INSIGHTS INTO T CELL MIGRATION IN RCC. ACHIEVEMENT OF THESE AIMS WILL UNCOVER THE ROLE OF THE TDLN AND EXHAUSTED CD8+ T CELL POPULATIONS IN SUSTAINING ANTI-TUMOR IMMUNITY, ASSESS THEIR RELEVANCE TO RCC AND OTHER SOLID TUMORS, AND IDENTIFY KEY T CELL SUBSETS AS CANDIDATES FOR ADOPTIVE CELL THERAPY. THE COLLABORATIVE ENVIRONMENT AT YALE UNIVERSITY, PAIRED WITH STATE-OF-THE-ART RESOURCES AND FACILITIES, ALONG WITH THE DEDICATED MENTORSHIP OF DR. BRAUN AND DR. BOSENBERG, PROVIDES AN IDEAL SETTING TO COMPLETE THIS RESEARCH AND DEVELOP INTO AN INDEPENDENT INVESTIGATOR.