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 tumor growth and patient outcome, but drug resistance continues to be problematic. One approach to deal with the challenge of resistance entails extending anti-cancer treatments beyond targeting cancer cells by additionally altering the tumor microenvironment. Understanding how the tumor microenvironment contributes to the evolution of diverse resistance pathways could aid in the design of sequential treatments that can elicit and take advantage of a 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 with fluorescent markers to track the stage-specific changes in macrophages under targeted therapy with Braf/Mek inhibitors and assessed the dynamic evolution of the macrophage population generated by therapy pressure-induced stress. During the onset of a drug-tolerant persister state, Ccr2+ monocyte-derived macrophage infiltration rose, suggesting that macrophage influx at this point could facilitate the onset of stable drug resistance. Comparison of melanomas that develop in a Ccr2-proficient or deficient microenvironment demonstrated that lack of melanoma infiltrating Ccr2+ macrophages delayed onset of resistance and shifted melanoma cell evolution towards unstable resistance. Unstable resistance was characterized by sensitivity to targeted therapy when factors from the microenvironment were lost. Importantly, this phenotype was reversed by co-culturing melanoma cells with Ccr2+ macrophages. Overall, this study demonstrates that the development of resistance may be directed by altering the tumor microenvironment to improve treatment timing and the probability of relapse.

New insights into the role of macrophages in cancer immunotherapy

“…Recruitment of monocytes from bone marrow to the tumor site is dependent on C-C motif ligand 2 (CCL2)-CC chemokine receptor 2 (CCR2) signal transduction (53). Inhibition of CCR2 causes monocyte retention in bone marrow and leads to depletion of monocytes in the peripheral circulation, reduction of monocyte recruitment to the primary tumor sites and metastatic foci, and consequent reduction of TAM number, resulting in tumor shrinkage and survival improvement (54)(55)(56).…”

Diapause-like Drug-Tolerant Persister State: The Key to Nirvana Rebirth

“…Growth and differentiation factor 15 (GDF-15) belongs to the transforming growth factor-β (TGF-β) superfamily of proteins, and it plays a role in the pathogenesis of tumors [25]. The expression/secretion of GDF-15 can only be detected in a DTP state, and GDF15 is not expressed or secreted in sensitive cells (parents) and completely resistant cells [26].…”

Tumor associated macrophages as key contributors and targets in current and future therapies for melanoma

“…TAMs often support neoplastic growth through their contribution to development of treatment resistance [ 127 ]. In vivo BRAF-mutant melanoma models with fluorescent markers to track stage-specific changes in macrophages under targeted therapy with BRAFi/MEKi, showed a rise in CCR2+ macrophage infiltration at the onset of a drug-tolerant persister (DTP) state after several weeks of treatment [ 127 ].…”