Project Grant R01CA285726

CD200R BLOCKADE FOR CANCER IMMUNOTHERAPY - PROJECT SUMMARY IMMUNOTHERAPIES BASED ON THE BLOCKADE OF IMMUNE CHECKPOINTS HAVE REVOLUTIONIZED CANCER TREATMENT IN RECENT YEARS. TODAY, IMMUNE CHECKPOINT INHIBITORS IN DEVELOPMENT AIM TO REACTIVATE TUMOR-INFILTRATING T CELLS TO FACILITATE TUMOR CELL DEATH. IN MANY TUMOR TYPES, HOWEVER, THE MOST ABUNDANT FORM OF INFILTRATING IMMUNE CELLS ARE MYELOID CELLS, SUCH AS MACROPHAGES, NEUTROPHILS, AND EOSINOPHILS, WHICH CAN BE TUMORICIDAL AS WELL AS TUMOR PROMOTING. CONSEQUENTLY, TARGETING IMMUNE CHECKPOINTS THAT REGULATE BOTH T CELLS AND MYELOID CELLS MAY HAVE BROAD IMPLICATIONS FOR CANCER IMMUNOTHERAPY. CD200R, INITIALLY IDENTIFIED AS A MYELOID-RESTRICTED, INHIBITORY IMMUNE RECEPTOR, WAS LATER ALSO DISCOVERED TO BE EXPRESSED WITHIN THE LYMPHOID LINEAGE, ESPECIALLY IN TUMOR-INFILTRATING EFFECTOR T CELLS. CLINICAL TRIALS OF PATIENTS WITH ADVANCED CANCERS ARE UNDERWAY USING ANTIBODY THERAPEUTICS TO BLOCK THIS PATHWAY. UNFORTUNATELY, A LACK OF UNDERSTANDING OF HOW THIS PATHWAY WORKS IN THE TUMOR MICROENVIRONMENT (TME) SUBSTANTIALLY COMPROMISES ITS APPLICATION IN CANCER IMMUNOTHERAPY. IN OUR RECENT STUDIES, WE FOUND THAT CD200R-DEFICIENT MICE WERE SIGNIFICANTLY MORE EFFICIENT IN REJECTING MULTIPLE LINEAGES OF CD200+ TUMORS. CD200R-DEFICIENCY RESULTED IN THE DYSREGULATION OF CHEMOKINES IN MYELOID CELLS, CONSISTENT WITH FEWER NEUTROPHILS AND MORE EOSINOPHILS AND OTHER IMMUNE EFFECTORS IN TUMORS. ADDITIONALLY, WE FOUND THAT CD200R-DEFICIENT TUMOR ANTIGEN-SPECIFIC T CELLS HAD A UNIQUE PHENOTYPE AND SHOWED MORE POTENT ANTI-TUMOR ACTIVITY IN VIVO. INTRIGUINGLY, CD200R-DEFICIENCY IN MYELOID CELLS ALSO PROMOTED TUMOR ANGIOGENESIS. THE OVERALL GOALS OF THIS PROPOSAL ARE TO TEST THE HYPOTHESES THAT CD200R BLOCKADE ENHANCES CHEMOKINE-MEDIATED ACCUMULATION OF IMMUNE EFFECTORS IN TUMORS AND ENHANCES T CELL FUNCTIONS IN TME, AND SIMULTANEOUS INHIBITION OF ANGIOGENESIS WILL SIGNIFICANTLY IMPROVE THE EFFICACY OF CD200R BLOCKADE THERAPY. TO ACHIEVE THESE GOALS, WE WILL FIRST EVALUATE THE ROLES OF KEY CHEMOKINES REGULATED BY CD200R SIGNALING IN RECRUITING IMMUNE EFFECTORS TO TUMORS AND INVESTIGATE THEIR ROLES IN TUMOR ANGIOGENESIS (AIM 1). SECOND, WE WILL USE MICE WITH CD200R- DEFICENCY IN T CELLS TO EVALUATE THE INTRINSIC ROLES OF CD200R SIGNALING IN REGULATING T CELL ACCUMULATION AND FUNCTION IN TUMORS (AIM 2). THESE TWO AIMS WILL PAVE THE WAY TOWARDS A THIRD TEST ON WHETHER HIGH AFFINITY ANTAGONIST ANTIBODY TO CD200R HAS BETTER EFFICACY, AND IF CD200R BLOCKADE AND ANGIOGENESIS INHIBITORS HAVE SYNERGISTIC EFFECTS IN INHIBITING TUMOR GROWTH (AIM 3). INFORMATION GENERATED FROM THESE STUDIES WILL NOT ONLY ADVANCE OUR UNDERSTANDING OF CANCER PATHOGENESIS BUT ALSO PAVE THE WAY FOR HUMAN TRIALS OF CD200R BLOCKADE- BASED COMBINATION THERAPIES.