Monitoring melanoma patients on treatment reveals a distinct macrophage population driving targeted therapy resistance

Resistance to targeted therapy remains a major clinical challenge in melanoma patients. To uncover resistance mechanisms, we performed single cell RNA sequencing of fine needle aspirates from resistant and responding tumors from melanoma patients before and during BRAFi/MEKi treatment. Among the genes most differentially expressed between malignant cells from resistant vs. responding tumors was POSTN encoding the secreted factor periostin. POSTN was predicted to predominantly signal to a macrophage population associated with targeted therapy resistance (TTR). Accordingly, tumors from patients with fast disease progression after targeted therapy exhibited high POSTN expression levels as well as high numbers of TTR macrophages, and POSTN was able to polarize macrophages towards a TTR phenotype. In a mouse model in vivo, POSTN expression protected melanoma from targeted therapy, which was associated with a phenotype change of intratumroal macrophages. Finally, polarized TTR macrophages protected melanoma cells from MEKi-induced killing through CD44 receptor expression on melanoma cells. Thus, interfering with the protective activity of TTR macrophages might represent a strategy to overcome resistance to targeted therapy in melanoma.