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

Although treatment of melanoma patients with BRAF and MEK inhibitors has demonstrated impressive clinical outcomes, innate or acquired resistance to targeted therapy remains a major challenge. To uncover resistance mechanisms in patients, we performed single cell RNA sequencing of longitudinal biopsies of the same tumors from four consenting melanoma patients before the start of BRAFi/MEKi treatment and at different time points during treatment. Among the genes most differentially expressed between malignant cells from resistant vs. responding patients was POSTN encoding the secreted factor periostin. POSTN was predicted to predominantly signal to a macrophage population associated with targeted therapy resistance (TTR) in patients and was able to polarize macrophages towards a TTR phenotype. Finally, polarized TTR macrophages protected melanoma cells from MEKi-induced killing, which involved CD44 receptor expression on melanoma cells. Thus, interfering with the protective activity of TTR macrophages might represent a strategy to overcome targeted therapy resistance in melanoma. Fine needle aspirates from melanoma tumors of 4 patients at baseline up to 4 during BRAF MEK inhibitor treatment, due to human data raw files will be available upon request >>Submitter states: Raw data couldn't be included due patient privacy concerns. Requests can be made to the PI for access to the raw data.<<<