Project Grant R03HL173146

CXCL9/10 MACROPHAGE INDUCED CXCR3+ T-CELL RECRUITMENT TO THE HEART CONTRIBUTES TO IMMUNOTHERAPY MYOCARDITIS - PROJECT SUMMARY/ABSTRACT IMMUNE CHECKPOINT INHIBITORS (ICIS) ARE MONOCLONAL ANTIBODIES USED AS NOVEL CANCER THERAPEUTICS TO RELEASE INTRINSIC BRAKES ON T-CELL CYTOTOXICITY AGAINST TUMOR CELLS. WHILE EFFECTIVE TO TREAT MANY ADVANCED CANCERS, ICIS HAVE BEEN REPORTED TO CAUSE FULMINANT MYOCARDITIS, PATHOLOGIC INFLAMMATION OF THE HEART-A LIFE-THREATENING SIDE EFFECT WHICH CAN LEAD TO SEVERE ARRHYTHMIAS, HEART FAILURE AND DEATH. ALTHOUGH OUR GROUP AND OTHERS HAVE PREVIOUSLY FOUND EFFECTOR CD8+ T-CELL CLONAL EXPANSION AND ACTIVATION IN THE HEART IN ICI MYOCARDITIS, THE CONTRIBUTION OF MACROPHAGES WITH RESPECT TO THEIR EFFECT ON T-CELLS HAS YET TO BE FULLY CHARACTERIZED. USING SINGLE- CELL RNA-SEQ DATA COLLECTED AS PART OF MY FUNDED K08, I HAVE FOUND AN ENRICHMENT OF CXCL9/10+ MACROPHAGES AND CXCR3+ EFFECTOR CD8+ T-CELLS IN THE HEARTS OF MRL/PDCD-1/- MICE WITH MYOCARDITIS. FURTHERMORE, DEPLETION OF MACROPHAGES IN MRL-PDCD1-/- MICE REDUCES CARDIAC CD8+ T-CELL INFILTRATION AND IMPROVES MICE SURVIVAL. THUS, I HYPOTHESIZE THAT RECRUITMENT OF CXCR3+ T-CELLS TO THE HEART BY CXCL9/CXCL10 EXPRESSING MACROPHAGES PLAYS A PATHOGENIC ROLE IN ICI MYOCARDITIS. TO TEST THIS, I WILL UTILIZE A NOVEL PHARMACOLOGICALLY TREATED MOUSE MODEL OF ICI MYOCARDITIS DEVELOPED IN MY LABORATORY, ALONG WITH HIGH THROUGHPUT IMMUNOPHENOTYPING TECHNIQUES AND IN VITRO PHENOTYPING. AIM 1 WILL INVESTIGATE THE EFFECTS OF CXCR3+ BLOCKADE IN OUR MOUSE MODEL OF ICI MYOCARDITIS, WHILE AIM 2 WILL INVESTIGATE THE MECHANISTIC EFFECTS OF BLOCKING CXCR3 AND ITS LIGANDS, CXCL9/10, ON MACROPHAGE-MEDIATED T-CELL MIGRATION AND FUNCTION IN AN IN VITRO TRANSWELL SYSTEM. THIS PROPOSAL HAS BEEN CAREFULLY DESIGNED TO BE FULLY ACHIEVABLE WITHIN THE TIMESPAN OF TWO YEARS OF THIS PROPOSAL, WHILE ALSO HAVING CRITICAL AND HIGH IMPACT IN THE FIELDS OF ICI MYOCARDITIS AND CARDIAC INFLAMMATION. BY COMPLETING THIS PROJECT, I WILL DEFINE KEY PATHOGENIC INTERACTIONS BETWEEN ADAPTIVE AND INNATE IMMUNITY WHICH DRIVE ICI MYOCARDITIS, BRIDGING A MAJOR KNOWLEDGE GAP IN THE ROLE OF MACROPHAGE EFFECTS ON T-CELL TRAFFICKING TO THE HEART IN MYOCARDITIS. IN DOING SO, I HOPE TO PAVE THE WAY FOR THE DEVELOPMENT OF ADJUVANT THERAPIES FOR TREATMENT AND PREVENTION OF ICI MYOCARDITIS. THIS GRANT WILL BE INSTRUMENTAL IN LAUNCHING THE NEXT PHASE OF MY CAREER AND PREPARE ME TO SUCCESSFULLY COMPETE FOR R01 FUNDING IN THE FIELD OF CARDIO-IMMUNOLOGY AND CARDIAC INFLAMMATION.