| Summary: | Immune checkpoint inhibitors (ICIs) have revolutionized the care for cancer and extended survival for many patients. While ICIs have shown astonishing clinical benefits, less than 50% of patients experience a durable response. To find better biomarkers for ICI response and understand the diverse cellular players in the tumor, we performed a multi-omic study on a metastatic melanoma cohort with RNA sequencing (39 samples), single cell RNA sequencing (222,351 cells; 39 samples), and single nucleus transposase-accessible chromatin sequencing (45,478 cells; 15 samples). We identified marker genes and functional modules associated with ICI response (e.g. cell-adhesion) and resistance (e.g. oxidative phosphorylation). Through single cell study of ICI resistant tumors, we revealed how cell-adhesion and ribosomal activity changes in the adaptive immunity could reflect tumor-level therapeutic failure. We further characterized the T cell diversity in the tumors and discovered an early activated state and a terminally exhausted T cell state with therapeutic potential. Among the innate immune mediators of tumor microenvironment, we detected a mature dendritic cell state as a powerful predictor of survival and extensively studied its differentiation trajectory, transcriptome signatures, and epigenome landscape. With functional roles in strengthening cancer immunity, many of the molecular and cellular mediators found in this study are relevant to the efficacy of all ICI regimens, and could potentially be extended to targeted inhibitors or other immunotherapies.
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