Project Grant R21CA282851

ESTROGEN SUPPRESSION AS A STRATEGY TO ENHANCE IMMUNOTHERAPY EFFICACY IN EGFR-MUTATED NON-SMALL CELL LUNG CANCER - PROJECT SUMMARY NON-SMALL CELL LUNG CANCER (NSCLC) AMONG NEVER-SMOKERS IS ON THE RISE. MUTATIONS IN THE EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR) GENE ARE COMMON AND FOUND IN >50% OF LUNG TUMORS FROM NEVER-SMOKERS. WHILE EGFR- MUTANT TUMORS EXHIBIT ROBUST RESPONSES TO TYROSINE KINASE INHIBITORS, DISEASE PROGRESSION IS UNFORTUNATELY INEVITABLE. MANY PATIENTS WITH STAGE IV NSCLC NOW EXPERIENCE DURABLE RESPONSES AND LONG-TERM SURVIVAL FOLLOWING TREATMENT WITH CHECKPOINT INHIBITORS. HOWEVER, SUCH BENEFITS ARE RARELY SEEN IN PATIENTS WITH EGFR- MUTANT DISEASE, WHERE RAPID DISEASE PROGRESSION IS FREQUENTLY OBSERVED. THE POOR RESPONSES TO CHECKPOINT INHIBITORS IN EGFR-MUTANT NSCLCS ARE LIKELY DUE TO THEIR IMMUNOSUPPRESSED "COLD" TUMOR MICROENVIRONMENT (TME), CHARACTERIZED BY LOW LEVELS OF INFILTRATING CD8+ AND CD4+ T CELLS AND HIGH LEVELS OF REGULATORY T CELLS (TREGS) AND M2 MACROPHAGES. AN UNMET NEED EXISTS TO ELUCIDATE THE FACTORS THAT CONTRIBUTE TO THE IMMUNOSUPPRESSED TME AND DEVELOP EFFICACIOUS IMMUNOTHERAPEUTIC REGIMENS FOR PATIENTS WITH EGFR-MUTANT NSCLC. EMERGING DATA SUGGEST ESTROGEN CONTRIBUTES TO AN IMMUNOSUPPRESSIVE TME. DATA FROM OTHER CANCER TYPES DEMONSTRATE THE ABILITY OF 17B-ESTRADIOL (E2) TO REGULATE SEVERAL IMMUNE CELL TYPES, INCLUDING CD8+ T CELLS, FOXP3+ TREGS, MACROPHAGES, AND NEUTROPHILS. ALTHOUGH IT IS WELL ESTABLISHED THAT ESTROGEN AND ITS REACTIVE METABOLITE 4-HYDROXYESTROGEN (4-OHE) PLAY AN IMPORTANT ROLE IN LUNG TUMORIGENESIS, LITTLE ATTENTION HAS BEEN GIVEN TO THEIR CONTRIBUTION TO IMMUNOSUPPRESSION IN THE LUNG TME OR THE USE OF ESTROGEN-MODULATING AGENTS TO ATTENUATE THESE EFFECTS. PRELIMINARY DATA FROM OUR GROUP DEMONSTRATE FOR THE FIRST TIME THAT ADMINISTRATION OF AN AROMATASE INHIBITOR (AI) TO MUTEGFRL858R MICE SIGNIFICANTLY INCREASES INTRA-TUMORAL CD8+ T CELL INFILTRATION AND PROMOTES ANTI-TUMOR EFFECTS. FURTHERMORE, OUR NEW DATA ARE THE FIRST TO DEMONSTRATE THAT: 1) DELETION OF CYP1B1 (ENZYME RESPONSIBLE FOR 4-OHE PRODUCTION) IN MUTEGFRL858R MICE REDUCES LUNG TUMOR BURDEN BY ~50%; 2) 4- OHE PRODUCTION IS SIGNIFICANTLY ENHANCED IN PATIENTS WITH EGFR-MUTANT NSCLC AS COMPARED TO HEALTHY CONTROLS; AND 3) 4-OHES POLARIZE MACROPHAGES TO THE IMMUNOSUPPRESSIVE M2 PHENOTYPE, AN IMMUNE SPECIES KNOWN TO BE ENRICHED IN EGFR-MUTANT TUMORS. THESE NOVEL DATA PROVIDE STRONG RATIONALE FOR INVESTIGATING THE USE OF AN AI WITH ANTI-PD1 THERAPY IN EGFR-MUTANT NSCLC. THE PROPOSED MULTIDISCIPLINARY RESEARCH WILL INVOLVE STUDIES IN THE MOUSE MODELS OF MUTEGFRL858R AND DELEGFRDL747-S752 LUNG ADENOCARCINOMA (AIM 1), COMPLEMENTED BY IMMUNE BIOMARKER ANALYSES USING ARCHIVED SPECIMENS FROM PATIENTS WITH EGFR-MUTANT NSCLC (AIM 2). RESEARCH UNDER BOTH AIMS WILL BE PERFORMED IN PARALLEL, TO FACILITATE RAPID TRANSLATION OF THE RESULTING DATA TO A CLINICAL SETTING AND SELECTION OF THE PATIENT POPULATION THAT WILL BENEFIT MOST FROM AN ESTROGEN MODULATOR. FINDINGS WILL ENHANCE OUR UNDERSTANDING OF THE CONTRIBUTION OF ESTROGEN AND ITS METABOLITES TO IMMUNOSUPPRESSION IN THE TME OF EGFR-MUTANT NSCLCS, AND INFORM THE DESIGN OF A NOVEL CLINICAL TRIAL THAT EMPLOYS AN AI WITH A CHECKPOINT INHIBITOR TO IMPROVE LONG-TERM SURVIVAL.