Project Grant R21CA293766

UNRAVELING VASCULAR MEDIATED IMMUNE EXCLUSION IN MELANOMA - TITLE: UNRAVELING VASCULAR MEDIATED IMMUNE EXCLUSION IN MELANOMA PROJECT SUMMARY MELANOMA REMAINS THE PRIMARY CAUSE OF SKIN CANCER-RELATED DEATHS. A SIGNIFICANT NUMBER OF PATIENTS SHOW RESISTANCE TO CHECKPOINT INHIBITORS, WHILE OTHERS EXPERIENCE DISEASE PROGRESSION AFTER INITIAL TREATMENT BENEFITS. A DEEPER UNDERSTANDING OF THE MECHANISMS UNDERLYING TUMOR IMMUNE SUPPRESSION IS ESSENTIAL. EFFECTIVE IMMUNOTHERAPY NOT ONLY DEPENDS ON CANCER-SPECIFIC T CELLS BUT ALSO ON THEIR DIRECT CONTACT WITH TUMOR CELLS. THE EXCLUSION OF IMMUNE EFFECTOR CELLS, SUCH AS CYTOTOXIC T CELLS, FROM THE TUMOR PARENCHYMA HAS BEEN LINKED TO REDUCED IMMUNOTHERAPY RESPONSE. HOWEVER, THE EXACT BIOLOGY BEHIND THIS PATTERN IN THE TUMOR MICROENVIRONMENT HAS YET TO BE FULLY UNDERSTOOD. RECENT RESEARCH EMPHASIZES THE POTENTIAL OF TARGETING THE TUMOR VASCULATURE TO IMPROVE TUMOR IMMUNE SUPPRESSION. THE INCREASED VASCULAR LEAKINESS ASSOCIATED WITH VASCULAR DESTABILIZATION HAS BEEN SUGGESTED TO HINDER IMMUNE EFFECTOR CELL INFILTRATION INTO TUMORS. ANGIOPOIETIN- 2 (ANGPT2), A THERAPEUTIC TARGET FOR MANY CANCERS, REGULATES VASCULAR REMODELING BY MODULATING TIE2 RECEPTOR TYROSINE KINASE SIGNALING IN ENDOTHELIAL CELLS. OUR LATEST STUDY DEMONSTRATED THAT ANGPT2 PROMOTES T-CELL EXCLUSION FROM TUMOR CORES BY CAUSING VASCULAR DESTABILIZATION AT THE TUMOR PERIPHERY. THIS HIGHLIGHTS THE NEED FOR A COMPREHENSIVE ANALYSIS OF VASCULAR REGULATION IN TUMOR IMMUNE EXCLUSION AND A DEEPER UNDERSTANDING OF THE MOLECULAR MECHANISM THROUGH WHICH ANGPT2 AFFECTS T-CELL EXCLUSION IN MELANOMA. IN THIS PROPOSED STUDY, WE AIM TO INVESTIGATE THE VASCULAR DETERMINANTS OF IMMUNE EXCLUSION FROM THE TUMOR CORE IN MELANOMA. WE PLAN TO ELUCIDATE THE DEVELOPMENT OF IMMUNE EXCLUSIONS FOR DIFFERENT IMMUNE CELLS DURING MELANOMA PROGRESSION AND EXAMINE THE SPATIAL VASCULAR CHANGES IN CORRELATION WITH IMMUNE CELL POSITIONS (AIM 1). MOREOVER, WE WILL DETERMINE THE MOLECULAR MECHANISMS BEHIND ANGPT2-DRIVEN T-CELL EXCLUSION IN MELANOMA (AIM 2). THIS WILL INVOLVE ELUCIDATING THE RELATIONSHIP BETWEEN ANGPT2 EXPRESSION LEVELS, VASCULAR LEAKINESS, AND T-CELL EXCLUSION IN HUMAN MELANOMA TISSUES AND INVESTIGATING THE EFFECTS OF ANGPT2 INHIBITION ON THE DEVELOPMENT AND PROGRESSION OF T-CELL EXCLUSION USING MOUSE MELANOMA MODELS. EMPLOYING MULTI-OMICS METHODS, WE AIM TO DECIPHER THE MOLECULAR MECHANISMS THROUGH WHICH VASCULAR ABNORMALITIES CONTRIBUTE TO IMMUNE EXCLUSION IN THE TUMOR MICROENVIRONMENT OF MELANOMA. OUR PROPOSED STUDY COULD IDENTIFY NOVEL TARGETS AND BIOMARKERS TO ADDRESS THE IMMUNE EXCLUSION, POTENTIALLY ENHANCING THE EFFECTIVENESS OF EXISTING IMMUNOTHERAPIES.