Abstract 5950: Ccr2+ monocyte derived macrophages influence trajectories of acquired therapy resistance in BRAF-mutant melanoma

Abstract

Therapies targeting oncogene addiction have had a tremendous impact on patient care, but drug resistance continues to be problematic. One method to deal with this challenge entails extending the scope of anti-cancer treatment beyond tumor cells by additionally altering their tumor microenvironment. Understanding how the tumor microenvironment can contribute to the evolution of diverse resistance pathways could aid in the rational design of sequential treatments that enforce pressure towards a more predictable resistance trajectory. Tumor associated macrophages often support neoplastic growth and are frequently the most abundant immune cell found in tumors. Here, we used clinically relevant in vivo Braf-mutant melanoma models and Ccr2-RFP; Cx3cr1-GFP mice to track the long-term changes in tumor cells and macrophages under targeted therapy with Braf/Mek inhibitors. We assessed the dynamic evolution of the macrophage population generated by therapy pressure-induced stress. During the onset of a drug-tolerant persister state, Ccr2+ macrophage infiltration rises, underscoring a prominent role at this point in melanoma evolution for development of drug-resistance. Importantly, we show that a lack of melanoma infiltrating Ccr2+ macrophages delays onset of resistance. In this case, rebounded tumor cells from Ccr2 knockout recipients favor the evolution of cell-extrinsic mediated resistance mechanisms, which can be reversed when these adapted melanoma cells are relocated to a microenvironment with functional Ccr2. Conversely, Ccr2 presence promotes development of cell-intrinsic drug resistance with a stable phenotype in rebounded tumor cells. Overall, this demonstrates that the development of resistance may be manipulated and directed to improve timing and probability of relapse. Citation Format: Dahihm Kim, Luye An, Jiwon Moon, Andrew White. Ccr2+ monocyte derived macrophages influence trajectories of acquired therapy resistance in BRAF-mutant melanoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5950.