Loss of ADAR1 in macrophages in combination with interferon gamma suppresses tumor growth by remodeling the tumor microenvironment

• DOI: 10.1136/jitc-2023-007402
• Publication Date: 2023-11-07T18:01:02Z
• Authors: Weiwei Lin; Yikai Luo; Jie Wu; Haowan Zhang; Ge Jin; Chahua Guo; Hang Zhou; Han Liang; Xiaoyan Xu
• Keywords: Cancer Immunotherapy

Background ADAR1, the major enzyme for RNA editing, has emerged as a tumor-intrinsic key determinant cancer immunotherapy efficacy through modulating interferon-mediated innate immunity. However, role of ADAR1 in immune cells such macrophages remains unknown. Methods We first analyzed publicly accessible patient-derived single-cell RNA-sequencing and perturbed sequencing data to elucidate expression function macrophages. Subsequently, we evaluated combined effects conditional knockout interferon (IFN)-γ treatment on tumor growth three distinct disease mouse models: LLC lung cancer, B16-F10 melanoma, MC38 colon cancer. To gain mechanistic insights, performed human cytokine arrays identify differentially secreted cytokines response perturbations THP-1 cells. Furthermore, examined loss IFN-γ vessel formation immunohistochemical staining sections tube-forming experiments using HUVEC SVEC4-10 also assessed CD8 + T immunofluorescent flow cytometry. explore translational potential, consequences injecting ADAR1-deficient alongside LLC-tumor-bearing mice. Results Our analysis public suggests that promotes antitumor immunity Indeed, with results regression diverse models. Mechanistically, leads differential secretion cytokines: it inhibits translation CCL20, GDF15, IL-18BP, TIM-3 by activating PKR/EIF2α signaling but increases transcriptional upregulation interleukin (IL)-18 due 5'UTR uORF. Consequently, decreased CCL20 GDF15 increased suppress angiogenesis, while IL-18BP IL-18 induce enhancing cytotoxicity further demonstrate combination therapy effectively suppresses tumors vivo. Conclusion This study provides comprehensive elucidation how within contributes establishment an microenvironment, suggesting therapeutic potential targeting beyond scope