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

作者全名："Chen, Yuru; Sun, Jiazheng; Liu, Jiazhou; Wei, Yuxian; Wang, Xiaoyu; Fang, Huiying; Du, Huimin; Huang, Jing; Li, Qin; Ren, Guosheng; Wang, Xiaoyi; Li, Hongzhong"

作者地址："[Chen, Yuru; Sun, Jiazheng; Liu, Jiazhou; Wang, Xiaoyu; Fang, Huiying; Ren, Guosheng; Li, Hongzhong] Chongqing Med Univ, Affiliated Hosp 1, Chongqing Key Lab Mol Oncol & Epigenet, Chongqing, Peoples R China; [Chen, Yuru; Sun, Jiazheng; Liu, Jiazhou; Wei, Yuxian; Wang, Xiaoyu; Ren, Guosheng; Wang, Xiaoyi] Chongqing Med Univ, Affiliated Hosp 1, Dept Endocrine & Breast Surg, Chongqing, Peoples R China; [Fang, Huiying] Chongqing Univ, Canc Hosp, Dept Breast Dis, Chongqing, Peoples R China; [Du, Huimin] Chongqing Med Univ, Affiliated Hosp 1, Dept Oncol, Chongqing, Peoples R China; [Huang, Jing] Chongqing Med Univ, Affiliated Hosp 1, Dept Resp, Chongqing, Peoples R China; [Li, Qin] Capital Med Univ, Beijing Friendship Hosp, Dept Oncol, Beijing, Peoples R China"

通信作者："Ren, GS; Li, HZ (通讯作者)，Chongqing Med Univ, Affiliated Hosp 1, Chongqing Key Lab Mol Oncol & Epigenet, Chongqing, Peoples R China.; Ren, GS; Wang, XY (通讯作者)，Chongqing Med Univ, Affiliated Hosp 1, Dept Endocrine & Breast Surg, Chongqing, Peoples R China."

来源：JOURNAL FOR IMMUNOTHERAPY OF CANCER

ESI学科分类：IMMUNOLOGY

WOS号：WOS:001122902400008

JCR分区：Q1

影响因子：10.3

年份：2023

卷号：11

期号：12

开始页：　

结束页：　

文献类型：Article

关键词：Breast Neoplasms; Immunity; Immunotherapy; Melanoma

摘要："BackgroundAldehyde 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.MethodsHere, 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.ResultsIn 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 of aldehyde downregulated the expression of V-domain Ig suppressor of T-cell activation (VISTA) via inactivating the nucleotide oligomerization domain (NOD)/nuclear factor kappa-B (NF-kappa B) signaling pathway. As a result, the cytotoxic function of CD8+ T cells was revitalized. Importantly, ALDH2 blockade markedly reinforced the efficacy of ICB treatment.ConclusionsOur data delineate that ALDH2-mediated aldehyde metabolism drives tumor immune evasion by activating the NOD/NF-kappa B/VISTA axis. Targeting ALDH2 provides an effective combinatorial therapeutic strategy for immunotherapy."

基金机构："National Natural Science Foundation of China [82173166, 81472475, 82273282, 82372886, 31420103915]; Natural Science Foundation of Chongqing [cstc2021jcyj- msxmX0015, CSTB2022NSCQ- MSX0783]; Chongqing medical scientific research project/Joint project of Chongqing Health Commission; Science and Technology Bureau [2021MSXM033, 2023QNXM039]; Chongqing Graduate Tutor Team Construction Project, Chongqing Education Commission Foundation [cqmudstd202216]; CQMU Program for Youth Innovation in Future Medicine [W0094]"

基金资助正文："This work was supported by the National Natural Science Foundation of China (No. 82173166, 81472475, 82273282, 82372886 and 31420103915), Natural Science Foundation of Chongqing (cstc2021jcyj- msxmX0015 and CSTB2022NSCQ- MSX0783), and Chongqing medical scientific research project/Joint project of Chongqing Health Commission and Science and Technology Bureau (NO.2021MSXM033 and 2023QNXM039), Chongqing Graduate Tutor Team Construction Project, Chongqing Education Commission Foundation (cqmudstd202216), and CQMU Program for Youth Innovation in Future Medicine (NO. W0094)."