Myeloid-T cell interplay and cell state transitions associated with checkpoint inhibitor response in melanoma

The treatment of melanoma, the deadliest form of skin cancer, has greatly benefited from immunotherapy. However, many patients do not show a durable response, which is only partially explained by known resistance mechanisms. We performed single-cell RNA sequencing of tumor immune infiltrates and matched peripheral blood mononuclear cells of 22 checkpoint inhibitor (CPI)-naive stage III–IV metastatic melanoma patients. After sample collection, the same patients received CPI treatment, and their response was assessed. CPI responders showed high levels of classical monocytes in peripheral blood, which preferentially transitioned toward CXCL9-expressing macrophages in tumors. Trajectories of tumor-infiltrating CD8+ T cells diverged at the level of effector memory/stem-like T cells, with non-responder cells progressing into a state characterized by cellular stress and apoptosis-related gene expression. Consistently, predicted non-responder-enriched myeloid-T/natural killer cell interactions were primarily immunosuppressive, while responder-enriched interactions were supportive of T cell priming and effector function. Our study illustrates that the tumor immune microenvironment prior to CPI treatment can be indicative of response. In perspective, modulating the myeloid and/or effector cell compartment by altering the described cell interactions and transitions could improve immunotherapy response. This research was funded by Roche Pharma Research and Early Development. [Display omitted] •Immune cell atlas of melanoma lesions and peripheral blood prior to immunotherapy•Monocytes are enriched in responders and transition into CXCL9+ macrophages•Non-responder-enriched myeloid-T/NK cell interactions are primarily immunosuppressive•Non-responder CD8+ T cells progress into a state of stress, apoptosis, and hypoxia There is an unmet need for deciphering cancer immunotherapy response-predicting factors and understanding mechanisms leading to treatment resistance. Researchers from Roche Pharma Research and Early Development and the University Hospital of Zurich have sequenced tumor and blood samples of melanoma patients before they received checkpoint inhibitor treatment. They have identified differences between patients responding and not responding to treatment, including distinct immune cell frequencies, differentiation states, and putative cell-cell interactions. Modulating the described patterns could improve the response to checkpoint inhibitors. Schlenker et al. g