Anti-PD-1 treatment response is associated with the influx of circulating myeloid and T-cell subsets into the metastatic melanoma tumor microenvironment

Background Immune checkpoint inhibition (ICI) significantly improves the survival of metastatic melanoma patients; however, a substantial proportion of patients does not respond to these breakthrough therapies. Methods To improve our understanding of this response variability, we developed high-plex panels for protein imaging of a discovery cohort and validation with RNAseq analyses to examine myeloid and T-cell subsets in pre-anti-PD-1-treatment samples of 14 metastatic melanoma patients (7 responders and 7 non-responders). Results We demonstrate that a higher abundance of circulating monocyte-derived macrophages (MDMs) and cytotoxic T-cell subsets in the tumor microenvironment (TME) at baseline distinguishes metastatic melanoma patients with a favorable response to anti-PD1 treatment from non-responders, who featured co-localization of suppressive macrophages (M2) and T-cells. Additionally, MDMs expressed high levels of immune checkpoints, and MDM infiltration into the TME was linked to both ICI response and survival. Conclusion These findings highlight the potential of MDM infiltration as a predictive biomarker for ICI response in metastatic melanoma.