Abstract 454: microRNAs role in innate immunosenescence during anti-PD1 immunotherapy

Abstract Checkpoint inhibitors have achieved durable responses and long-lasting immunologic memory in cancer patients. However, the initial and acquired resistance remains an unsolved problem. It’s urgent to learn the molecular mechanisms causing resistance. microRNAs (miRNAs) are short transcripts that regulate many pathophysiological processes. Here, we investigated the miRNAs expression changes after GVAX combined with monoclonal PD-1 antibody treatment in the murine melanoma B16F10 tumors and identified microRNAs down-regulated in responsive tumors. Deletion of this family member in three different syngeneic mouse tumors did not affect their in vitro nor in vivo proliferation but sensitized anti-PD1 immunotherapy. The miRNA deletion with anti-PD1 therapy increased total CD45+ leukocyte infiltration with all types of hematopoietic cells except macrophages. Both tumor bulk RNA sequencing and single-cell RNA sequencing revealed activated innate sensing genes especially for pathogen recognition and phagosome formation. Importantly, we found specific miRNA-deletion effects rely on tumor resident macrophage, IFN-γ release in the tumor microenvironment (TME) and the miRNA regulating machinery protein Argonaut2 (Ago2). Notably, the miRNA expression status of melanoma patients correlates with the survival and innate immune sensing gene expression. Our results suggest that this family of miRNAs participate in initial resistance by escaping innate immunosurveillance. Deletion of the miRNA may turn immune “cold” tumors to “hot” tumors, providing potential therapeutic targets to overcome resistance in melanoma, colorectal, triple-negative breast cancer and possibly other cancers. Citation Format: Zhouting Zhu, Tariq M. Rana. microRNAs role in innate immunosenescence during anti-PD1 immunotherapy abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 454.