Abstract B41: Reprogramming immunosuppressive tumor-associated macrophages potentiates standard-of-care therapy in melanoma

Abstract Cutaneous melanoma is a highly aggressive cancer capable of distant and lethal metastatic spread. Recent breakthroughs have come from understanding oncogenic signaling and cancer immunobiology. Targeted therapies successfully block MAPK signaling in BRAFV600e mutant melanoma with remarkably high clinical responses followed by rapid relapse, whereas checkpoint inhibitors activating the immune response induce long-lasting responses, albeit only in a subset of patients. These limitations have driven interest in understanding innate and acquired resistance. Using an immunocompetent genetically-engineered mouse model of BRAF-driven melanoma, which phenocopies the human disease in its development, histopathology, and response to therapy, we focused on the tumor microenvironment (TME), seeking to elucidate resistance mechanisms. Our investigations have revealed that tumor-associated macrophages (TAMs) are a critical component of the TME, predominantly polarized toward a pro-tumoral “M2-like” phenotype, producing immunosuppressive factors and exhibiting extensive immuno-suppressive capabilities suggesting that they might significantly hinder immune responses in the melanoma TME. Seeking to assess their functional importance, we have found that combining conventional strategies with TAMs-reprogramming agents stimulates anti-tumor immune responses, leading to improved survival and responsiveness to standard-of-care therapies. These data highlight the central role played by macrophages in melanoma progression and demonstrate that pharmacologic reprogramming of macrophages represents a new therapeutic modality with the potential to elicit more effective anti-tumor immune responses against this devastating disease. Citation Format: Melanie Tichet, Agnieszka Chryplewicz, Douglas Hanahan. Reprogramming immunosuppressive tumor-associated macrophages potentiates standard-of-care therapy in melanoma [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr B41.