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

August, 08, 2024 | Select Oncology Journal Articles

Background

ADAR1, the major enzyme for RNA editing, has emerged as a tumor-intrinsic key determinant for cancer immunotherapy efficacy through modulating interferon-mediated innate immunity. However, the role of ADAR1 in innate immune cells such as macrophages remains unknown.

Methods

We first analyzed publicly accessible patient-derived single-cell RNA-sequencing and perturbed RNA sequencing data to elucidate the ADAR1 expression and function in macrophages. Subsequently, we evaluated the combined effects of ADAR1 conditional knockout in macrophages and interferon (IFN)- treatment on tumor growth in three distinct disease mouse models: LLC for lung cancer, B16-F10 for melanoma, and MC38 for colon cancer. To gain the mechanistic insights, we performed human cytokine arrays to identify differentially secreted cytokines in response to ADAR1 perturbations in THP-1 cells. Furthermore, we examined the effects of ADAR1 loss and IFN- treatment on vessel formation through immunohistochemical staining of mouse tumor sections and tube-forming experiments using HUVEC and SVEC4-10 cells. We also assessed the effects on CD8+ T cells using immunofluorescent and immunohistochemical staining and flow cytometry. To explore the translational potential, we examined the consequences of injecting ADAR1-deficient macrophages alongside IFN- treatment on tumor growth in LLC-tumor-bearing mice.

Results

Our analysis on public data suggests that ADAR1 loss in macrophages promotes antitumor immunity as in cancer cells. Indeed, ADAR1 loss in macrophages combined with IFN- treatment results in tumor regression in diverse disease mouse models. Mechanistically, the loss of ADAR1 in macrophages leads to the differential secretion of key cytokines: it inhibits the translation of CCL20, GDF15, IL-18BP, and TIM-3 by activating PKR/EIF2α signaling but increases the secretion of IFN- through transcriptional upregulation and interleukin (IL)-18 due to the 5’UTR uORF. Consequently, decreased CCL20 and GDF15 and increased IFN- suppress angiogenesis, while decreased IL-18BP and TIM-3 and increased IL-18 induce antitumor immunity by enhancing cytotoxicity of CD8+ T cells. We further demonstrate that combination therapy of injecting ADAR1-deficient macrophages and IFN- effectively suppresses tumors in vivo.

Conclusion

This study provides a comprehensive elucidation of how ADAR1 loss within macrophages contributes to the establishment of an antitumor microenvironment, suggesting the therapeutic potential of targeting ADAR1 beyond the scope of cancer cells.

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