Project Grant F31CA310579

TARGETING MITOCHONDRIAL STRESS RESPONSES IN MELANOMA TO ENHANCE IMMUNOTHERAPY - PROJECT SUMMARY METASTATIC MELANOMA IS A LATE-STAGE FORM OF CUTANEOUS MELANOMA THAT HAS POOR PROGNOSIS IN PATIENTS DESPITE MULTIPLE AVAILABLE TREATMENT OPTIONS. THE MOST COMMON THERAPY FOR THIS MALIGNANCY IS IMMUNE CHECKPOINT BLOCKADE (ICB), BUT MANY TREATED PATIENTS FAIL TO SHOW LONG-TERM RESPONSES. THE IMMUNOSUPPRESSIVE TUMOR MICROENVIRONMENT (TME) ORCHESTRATED BY CUTANEOUS MELANOMA REPRESENTS A PRIMARY MECHANISM FOR THE EVASION OF ANTI-TUMOR REACTIVITY AND IS A MAJOR CHALLENGE FOR THE SUCCESSFUL DEVELOPMENT OF ICB STRATEGIES. THE TME IS CHARACTERIZED BY MULTIPLE CELLULAR STRESS TRIGGERS THAT IMPACT BOTH TUMOR AND STROMAL POPULATIONS. MELANOMA CELLS GO THROUGH CELLULAR STRESS ADAPTATION PROCESSES TO SURVIVE, PROLIFERATE, AND MIGRATE. ONE OF THE KEY PROCESSES USED TO ADAPT TO THE STRESSFUL TME IS THROUGH THE MITOCHONDRIA. THIS F31 PROPOSAL SEEKS TO UNDERSTAND THE ROLE OF THE MITOCHONDRIAL UNFOLDED PROTEIN RESPONSE (UPRMT) AS A FUNDAMENTAL MEDIATOR OF MELANOMA CELL SURVIVAL AND IMMUNE EVASION THROUGH A MULTI-OMICS APPROACH ALONG WITH CELL CULTURE AND MOUSE MODEL VALIDATIONS. OUR KEY PRELIMINARY RESULTS DEMONSTRATE THAT TARGETING A PROTEASE IN THE UPRMT, XPNPEP3, DRAMATICALLY IMPAIRS TUMOR GROWTH COMBINED WITH INCREASED INFILTRATION AND ACTIVATION OF PROTECTIVE IMMUNITY IN THE TME. THUS, THIS PROPOSAL WILL DETERMINE: 1) THE EFFECT OF THE ELIMINATION OF MELANOMA CELL- DERIVED XPP3 ON THE EXPANSION OF DENDRITIC CELLS (DCS) AND T CELLS, 2) THE MECHANISMS WHEREBY XPP3 ABLATION INDUCES IMMUNOGENIC CELL DEATH IN CANCER CELLS, AND 3) THE THERAPEUTIC TARGETING OF XPP3 WITH CURRENT ICB STRATEGIES. I HYPOTHESIZE THAT XPP3 ELIMINATION IN MELANOMA CELLS TRIGGERS ANTI-TUMOR IMMUNITY VIA IMMUNOGENIC CANCER CELL DEATH AND THAT THERAPEUTIC TARGETING XPP3 WILL BOOST CURRENT IMMUNOTHERAPIES BY DRIVING DC AND T CELL FUNCTIONALITY INTO THE TME. IMPORTANTLY, THIS TRAINING WILL SUPPORT MY DEVELOPMENT IN TUMOR IMMUNOLOGY AND BIOINFORMATICS. AS SUCH, THIS F31 PROPOSAL WILL UTILIZE CO-MENTORS DR. PAULO RODRIGUEZ AND DR. XUEFENG WANG FOR THEIR COMBINED EXPERTISE FOR TRAINING ON SINGLE CELL BIOINFORMATICS, IMMUNOLOGY, IMMUNOGENIC CELL DEATH AND IMMUNOTHERAPY. THIS WORK IS ANTICIPATED TO ELUCIDATE FOR THE FIRST TIME THE ROLE OF THE UPRMT MEDIATOR XPNPEP3 IN PROMOTING TUMOR CELL SURVIVAL AND SUBSEQUENT IMMUNE SUPPRESSION IN THE TME OF MELANOMA, ENABLING NEW THERAPIES THAT IMPACT MELANOMA PROGRESSION AND SYNERGIZE WITH ICB.