Project Grant K08CA279766

STRESS-INDUCED IMMUNOSUPPRESSION VIA DOWNREGULATION OF INTERFERON IN TRIPLE NEGATIVE BREAST CANCER - PROJECT SUMMARY TRIPLE NEGATIVE BREAST CANCER (TNBC) IS THE MOST AGGRESSIVE FORM OF BREAST CANCER (BC) WHICH OCCURS MORE FREQUENTLY IN YOUNGER WOMEN, OFTEN DIAGNOSED ONCE THE DISEASE HAS ALREADY METASTASIZED. IT IS THE ONLY BC SUBTYPE WHERE IMMUNE CHECKPOINT INHIBITORS (ICIS) ARE APPROVED FOR USE, BUT ONLY A MINORITY OF PATIENTS RESPOND TO CURRENT ICI TREATMENTS. ONE MECHANISM OF RESISTANCE IS LOW EXPRESSION OF INTRATUMORAL CHEMOKINES CXCL9 AND CXCL10, ESSENTIAL FOR ATTRACTING ANTI-TUMOR CD8+ T CELLS INTO THE TUMOR MICROENVIRONMENT (TME). PSYCHOSOCIAL STRESS, EXPERIENCED BY MANY BC PATIENTS CAN ENHANCE IMMUNOSUPPRESSION. B-ADRENERGIC RECEPTOR BLOCKADE HAS SHOWN HIGHER SURVIVAL BENEFIT IN TNBC PATIENTS COMPARED WITH OTHER BC SUBTYPES (OBSERVATIONAL STUDIES), SUGGESTING A POSSIBILITY OF SYMPATHETIC OVERDRIVE IN TNBC. HOWEVER, THE MECHANISTIC ROLE OF PSYCHOSOCIAL STRESS IN TREATMENT RESISTANCE TO ICIS AMONG TNBC PATIENTS REMAINS UNKNOWN. WE HAVE SHOWN THAT CHRONIC STRESS AND ITS MEDIATORS, EPINEPHRINE (EPI) AND NOREPINEPHRINE (NE), DRIVE IMMUNOSUPPRESSION IN THE TME BY DECREASING CD8+ T CELLS AND INCREASING MYELOID DERIVED SUPPRESSOR CELLS AND REGULATORY T CELLS. OUR SUBSEQUENT STUDY SHOWED THAT PROPRANOLOL, A PAN-B-BLOCKER, IMPROVES RESPONSE TO ICIS IN METASTATIC MELANOMA PATIENTS. WE ALSO FOUND THAT EPI CAN MEDIATE THE INDUCTION OF PROSTAGLANDIN E2 (PGE2) IN BC TISSUES. WE AND OTHERS HAVE SHOWN THAT PGE2 INHIBITS INTERFERON (IFN)-INDUCED CXCL9/10 SECRETION. THUS, I HYPOTHESIZE THAT CHRONIC STRESS PROMOTES IMMUNOSUPPRESSION IN TNBC BY INCREASING PGE2 AND INHIBITING IFN PATHWAYS, RESULTING IN DECREASED CXCL9/10. I PROPOSE TO TEST THIS HYPOTHESIS IN THE FOLLOWING AIMS: 1) EXAMINE NE-INDUCED CHANGES IN TNBC TISSUES AND TEST THERAPEUTIC MEASURES EX VIVO; 2) STUDY IMMUNE CHANGES IN PRE- VS. POST-TREATMENT TUMOR TISSUES AND BLOOD OF METASTATIC TNBC PATIENTS RECEIVING PROPRANOLOL AND ICI; AND 3) CORRELATE VALIDATED MEASURES OF PSYCHOSOCIAL STRESS WITH THE EXPRESSION OF IFNS AND CXCL9/10 IN BC TISSUES. TO ACHIEVE THESE GOALS, I WILL UTILIZE TNBC TISSUES FROM PATIENTS IN EX VIVO STUDIES, CONDUCT A PROSPECTIVE CLINICAL TRIAL, AND EXAMINE RELATIONSHIPS BETWEEN SELF-REPORTED STRESS AND CORRELATES OF TUMOR IMMUNITY IN BANKED SAMPLES. TO GAIN MECHANISTIC UNDERSTANDING, COMPLEMENTARY STATE-OF-THE-ART MULTIPLEX TISSUE IMAGING TECHNIQUES INCLUDING CONFOCAL MICROSCOPY, IMAGING MASS CYTOMETRY, AND SPATIAL TRANSCRIPTOMICS WILL BE UTILIZED. COMPLETION OF THE PROPOSED WORK WILL PROVIDE KEY NOVEL INSIGHTS INTO THE MECHANISTIC ROLE OF THE PGE2-IFN-CHEMOKINES PATHWAY IN STRESS-INDUCED TME IMMUNOSUPPRESSION AND HELP INFORM NEW APPROACHES THAT WILL BE TRANSLATED INTO ENHANCED THERAPEUTIC BENEFIT FOR TNBC PATIENTS. THIS PROJECT WILL ADVANCE MY DEVELOPMENT INTO AN INDEPENDENT CLINICAL SCIENTIST AND TRANSLATIONAL RESEARCHER ADVANCING PRECISION IMMUNO-ONCOLOGY TREATMENTS FOR TNBC. THIS WILL BE ACCOMPLISHED IN A RICH ACADEMIC ENVIRONMENT AT ROSWELL PARK COMPREHENSIVE CANCER CENTER AND UNIVERSITY AT BUFFALO UNDER THE GUIDANCE OF AN OUTSTANDING MENTORSHIP TEAM WITH COMPLEMENTARY EXPERTISE IN THE AREAS OF BREAST CANCER, IMMUNO-ONCOLOGY, TME-ASSOCIATED CHEMOKINES, PROSTAGLANDINS, IFNS, AND PSYCHOSOCIAL STRESS.