Aldehyde dehydrogenase 2-mediated aldehyde metabolism promotes tumor immune evasion by regulating the NOD/VISTA axis

作者：Yuru Chen, Jiazheng Sun, Jiazhou Liu, Yuxian Wei, Xiaoyu Wang, Xiaoyu Wang, Huiying Fang, Huimin Du, Jing Huang, Qin Li, Guosheng Ren, Xiaoyi Wang, Xiaoyi Wang, Hongzhong Li · 发表于：Journal for ImmunoTherapy of Cancer · 年份：2023 · DOI：10.1136/jitc-2023-007487 · 被引用次数：30 · 研究领域：Alcohol Consumption and Health Effects、Cancer Cells and Metastasis、Cancer, Hypoxia, and Metabolism

Background Aldehyde dehydrogenase 2 (ALDH2) is a crucial enzyme involved in endogenous aldehyde detoxification and has been implicated in tumor progression. However, its role in tumor immune evasion remains unclear. Methods Here, we analyzed the relationship between ALDH2 expression and antitumor immune features in multiple cancers. ALDH2 knockout tumor cells were then established using CRISPR/Cas9 system. In immunocompetent breast cancer EMT6 and melanoma B16-F10 mouse models, we investigated the impact of ALDH2 blockade on cytotoxic T lymphocyte function and tumor immune microenvironment by flow cytometry, mass cytometry, Luminex liquid suspension chip detection, and immunohistochemistry. Furthermore, RNA sequencing, flow cytometry, western blot, chromatin immunoprecipitation assay, and luciferase reporter assays were employed to explore the detailed mechanism of ALDH2 involved in tumor immune evasion. Lastly, the synergistic therapeutic efficacy of blocking ALDH2 by genetic depletion or its inhibitor disulfiram in combination with immune checkpoint blockade (ICB) was investigated in mouse models. Results In our study, we uncovered a positive correlation between the expression level of ALDH2 and T-cell dysfunction in multiple cancers. Furthermore, blocking ALDH2 significantly suppressed tumor growth by enhancing cytotoxic activity of CD8 + T cells and reshaping the immune landscape and cytokine milieu of tumors in vivo . Mechanistically, inhibiting ALDH2-mediated metabolism...