ALKBH5 regulates anti-PD-1 therapy response by modulating lactate and suppressive immune cell accumulation in tumor microenvironment
ALKBH5 regulates anti-PD-1 therapy response by modulating lactate and suppressive immune cell accumulation in tumor microenvironment
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DOI：
10.1073/pnas.1918986117
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发表时间：
2020-08-18
影响因子：
11.1
通讯作者：
Rana, Tariq M.
中科院分区：
文献类型：
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作者：
Li, Na;Kang, Yuqi;Rana, Tariq M.
虽然免疫检查点阻断(ICB)治疗已经使癌症治疗失败，但许多患者对ICB没有反应或产生抵抗力。RNA中腺苷(M6A)的N6-甲基化调节许多病理生理过程。在这里，我们展示了M6A去甲基酶Alkbh5的缺失使肿瘤对癌症免疫治疗敏感。在ICB过程中，Alkbh5对肿瘤的m6A密度和剪接事件有影响。Alkbh5可调节肿瘤微环境中MCT4/Slc16a3的表达和乳酸含量，调节肿瘤浸润性Treg细胞和髓系抑制细胞的组成。重要的是，一种小分子Alkbh5抑制剂增强了癌症免疫治疗的效果。值得注意的是，黑色素瘤患者的ALKBH5基因突变和表达状态与他们对免疫治疗的反应有关。我们的结果表明，肿瘤细胞中的m6A去甲基酶有助于免疫治疗的疗效，并确认ALKBH5是一个潜在的治疗靶点，可以提高淋巴瘤、结直肠癌和潜在的其他癌症的免疫治疗结果。
Although immune checkpoint blockade (ICB) therapy has revolu-tionized cancer treatment, many patients do not respond or develop resistance to ICB. N6-methylation of adenosine (m6A) in RNA regulates many pathophysiological processes. Here, we show that deletion of the m6A demethylase Alkbh5 sensitized tumors to cancer immunotherapy. Alkbh5 has effects on m6A density and splicing events in tumors during ICB. Alkbh5 modulates Mct4/Slc16a3 expression and lactate content of the tumor microenviron-ment and the composition of tumor-infiltrating Treg and myeloid -derived suppressor cells. Importantly, a small-molecule Alkbh5 in-hibitor enhanced the efficacy of cancer immunotherapy. Notably, the ALKBH5 gene mutation and expression status of melanoma patients correlate with their response to immunotherapy. Our re-sults suggest that m6A demethylases in tumor cells contribute to the efficacy of immunotherapy and identify ALKBH5 as a potential therapeutic target to enhance immunotherapy outcome in mela-noma, colorectal, and potentially other cancers.