Project Grant F31CA301844

UNRAVELING THE MECHANISMS OF NEOANTIGEN VACCINE-INDUCED EPITOPE SPREADING - PROJECT ABSTRACT THE ADVENT OF IMMUNOTHERAPY HAS RESHAPED OUR APPROACH TO CANCER TREATMENT, WITH LASTING CURES ACHIEVED IN A SUBSET OF PATIENTS. TUMOR NEOANTIGEN VACCINES HAVE BEEN SHOWN TO EFFECTIVELY PRIME TUMOR-DIRECTED T CELL RESPONSES AND INDUCE EPITOPE SPREADING (ES), A PHENOMENON LINKED TO IMPROVED CLINICAL OUTCOME. ES OCCURS WHEN VACCINE-INDUCED TUMOR CELL LYSIS RELEASES ADDITIONAL TUMOR ANTIGENS, WHICH SUBSEQUENTLY PRIMES A NEW WAVE OF TUMOR-SPECIFIC T CELLS. HOWEVER, TECHNICAL CHALLENGES HAVE RESTRICTED THE EVALUATION OF ES TO ONLY SMALL SETS OF KNOWN TARGET ANTIGENS, WHILE IT REMAINS UNKNOWN HOW T CELLS PRIMED THROUGH VACCINES DIFFER PHENOTYPICALLY FROM NATURALLY PRIMED (VIA ES) T CELLS, AND WHAT TYPES OF T CELL - TARGET CELL INTERACTIONS ARE FAVORED WITH RESPECT TO THEIR FUNCTIONAL AVIDITIES. IN ADDITION, ES TO NOVEL NON-CANONICAL ANTIGENS, SUCH AS NON-CANONICAL OPEN READING FRAMES (NUORFS), STRUCTURAL VARIANTS (SVS), AND TRANSPOSABLE ELEMENTS (TES) MAY ALSO CONTRIBUTE TO ANTI-TUMOR T CELL RESPONSES WHEN CONVENTIONAL ANTIGENS (DERIVED FROM POINT MUTATIONS AND SHORT INSERTIONS AND DELETIONS) ARE SCARCE. IN RECENT YEARS, THE WU AND SCHUMACHER GROUPS HAVE DEVELOPED A SET OF IMMUNOGENOMICS-BASED TOOLS, WHICH PROVIDE NEW APPROACHES TO ADDRESS THESE UNRESOLVED QUESTIONS. SPECIFICALLY, WE HAVE DEVELOPED NEOANTIGEN PREDICTION PIPELINES FACILITATING THE IDENTIFICATION OF ANTIGENS FROM WHOLE-EXOME SEQUENCING DATA AND MASS SPECTROMETRY. FURTHER, WE HAVE REFINED OUR ANTIGEN DISCOVERY ABILITIES, BY FOCUSING ON THE DETECTION OF POTENTIAL ANTIGENS DERIVED FROM NON-CANONICAL ANTIGENS. FINALLY, WE HAVE CONCEIVED HANSOLO AND PAIR-SCAN, NOVEL LIBRARY-BASED TOOLS CAPABLE OF GENERATING FUNCTIONAL, PAIRED TCR- ANTIGEN INFORMATION AT SCALE. WITH THESE CAPABILITIES, I PROPOSE TO THUS SYSTEMATICALLY DISSECT NEOANTIGEN VACCINE- INDUCED ES IN TWO DISTINCT SETTINGS: IN SPECIFIC AIM 1, I WILL SYSTEMATICALLY EVALUATE ES IN MELANOMA, A TUMOR TYPE CHARACTERIZED BY A HIGH TUMOR MUTATIONAL BURDEN (TMB). I HYPOTHESIZE THAT VACCINE-INDUCED ES GENERATES T CELLS OF MEMORY-LIKE PHENOTYPE CHARACTERIZED BY A DEFINED SPECTRUM OF FUNCTIONAL AVIDITIES TOWARDS THEIR RESPECTIVE TARGET ANTIGENS, RESULTING IN ENHANCED TUMOR CONTROL. IN SPECIFIC AIM 2, I WILL EVALUATE THE IMMUNOGENICITY OF NON-CANONICAL ANTIGENS IN THE SETTING OF HIGH-GRADE SEROUS OVARIAN CANCER, A TUMOR WITH LOW TMB, YET RICH IN NUORFS, SVS, AND TE. I WILL FURTHERMORE ASSESS HOW POTENTIAL ES TO THESE NON-CANONICAL ANTIGENS MAY CONTRIBUTE TO DISEASE CONTROL. BY RELATING FEATURES UNDERLYING ES TO CLINICAL BIOMARKERS, I HOPE TO DETERMINE HOW THIS PHENOMENON IS RELATED TO POSITIVE CLINICAL OUTCOMES DURING CANCER IMMUNOTHERAPY.