Abstract 6430: Single-cell transcriptomic and epigenomic landscapes of innate and adaptive immune cells in metastatic melanoma treated with immunotherapy

Abstract

Abstract Immune checkpoint inhibitors (ICIs) have revolutionized the care for cancer and extended survival for advanced cancer 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 microenvironment (TME), we performed single-cell RNA sequencing (scRNA; 222,351 cells; 39 samples), single-nucleus transposase-accessible chromatin sequencing (scATAC; 45,478 cells; 15 samples), and bulk RNA sequencing (39 samples) on a metastatic melanoma cohort with rich phenotypic and molecular data. In ICI resistant tumors, we revealed how cell-adhesion and ribosomal activity changes in adaptive immune cells can reflect tumor-level therapeutic failure. We characterized T cell diversity in the TME and discovered an early activated state and a terminally exhausted state. Among the innate immune cells, we detected a mature dendritic cell (DC) state as a strong prognostic predictor of progression-free survival associated with ICI treatment. We studied its differentiation trajectory, transcriptome signatures, epigenome landscape and interactome with T-cells, in comparison to conventional dendritic cell types 1 and 2. We also showed that CRISPR deactivation of the enhancers induced by the mature DC state compromised DCs’ antigen-presentation capabilities and their interactions with antigen-specific T-cells. Lastly, we identified genes and functional modules associated with ICI response (e.g. cell-adhesion) and resistance (e.g. oxidative phosphorylation). Given their functional roles in strengthening immune response to cancer, the molecular and cellular mediators discovered here can help predict ICI regimen efficacy, guide therapeutic development and drug combinations, and pave the path to targeted therapies with long-term effects and new immunotherapies. Citation Format: Jiekun Yang, Doris Fu, Kyriakitsa Galani, Li-Lun Ho, Emily J. Robitschek, Dennie T. Frederick, Sandeep K. Yadav, Wentao Deng, Anand K. Singh, Kelly P. Burke, Cassia Wang, Tatyana Sharova, David Liu, Kunal Rai, Genevieve M. Boland, Manolis Kellis. Single-cell transcriptomic and epigenomic landscapes of innate and adaptive immune cells in metastatic melanoma treated with immunotherapy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6430.