美国芝加哥大学Ralph R. Weichselbaum，Chuan He和Hua Laura Liang共同合作，近期取得重要工作进展。他们研究发现可以通过抑制YTHDF2来增强放疗抗肿瘤疗效。相关研究成果2023年5月25日在线发表于《癌细胞》杂志上。
据介绍，RNA N6-甲基腺苷（m6A）修饰与癌症进展有关。然而，m6A对放疗抗肿瘤作用的影响及其相关机制尚不清楚。
研究人员发现电离辐射（IR）在小鼠模型和人类中诱导免疫抑制性髓源性抑制细胞（MDSC）扩增和YTHDF2表达。IR后，髓系细胞中Ythdf2的缺失通过改变MDSC分化、抑制MDSC浸润和抑制功能来增强抗肿瘤免疫并克服肿瘤放射抗性。Ythdf2缺乏逆转了局部IR对MDSC种群的重塑。IR诱导的YTHDF2表达依赖于NF-κB信号传导；YTHDF2通过直接结合和降解编码NF-κB信号负调控因子的转录物，进而导致NF-κB活化，从而产生IR-YTHDF2-NF-κB-回路。YTHDF2的药理学抑制克服了MDSC诱导的免疫抑制，并改善了IR和/或抗PD-L1的联合治疗。
因此，YTHDF2是改善放疗（RT）和RT/免疫疗法组合的一个有前途的靶点。
附：英文原文
Title: YTHDF2 inhibition potentiates radiotherapy antitumor efficacy
Author: Liangliang Wang, Xiaoyang Dou, Shijie Chen, Xianbin Yu, Xiaona Huang, Linda Zhang, Yantao Chen, Jiaai Wang, Kaiting Yang, Jason Bugno, Sean Pitroda, Xingchen Ding, Andras Piffko, Wei Si, Chao Chen, Hualiang Jiang, Bing Zhou, Steven J. Chmura, Cheng Luo, Hua Laura Liang, Chuan He, Ralph R. Weichselbaum
Issue&Volume: 2023-05-25
Abstract: RNA N6-methyladenosine (m6A) modification is implicated in cancer progression. However, the impact of m6A on the antitumor effects of radiotherapy and the related mechanisms are unknown.Here we show that ionizing radiation (IR) induces immunosuppressive myeloid-derivedsuppressor cell (MDSC) expansion and YTHDF2 expression in both murine models and humans.Following IR, loss of Ythdf2 in myeloid cells augments antitumor immunity and overcomes tumor radioresistanceby altering MDSC differentiation and inhibiting MDSC infiltration and suppressivefunction. The remodeling of the landscape of MDSC populations by local IR is reversedby Ythdf2 deficiency. IR-induced YTHDF2 expression relies on NF-κB signaling; YTHDF2 in turnleads to NF-κB activation by directly binding and degrading transcripts encoding negativeregulators of NF-κB signaling, resulting in an IR-YTHDF2-NF-κB circuit. Pharmacologicalinhibition of YTHDF2 overcomes MDSC-induced immunosuppression and improves combinedIR and/or anti-PD-L1 treatment. Thus, YTHDF2 is a promising target to improve radiotherapy(RT) and RT/immunotherapy combinations.
DOI: 10.1016/j.ccell.2023.04.019
Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(23)00163-0
Cancer Cell：《癌细胞》，创刊于2002年。隶属于细胞出版社，最新IF：38.585
官方网址：https://www.cell.com/cancer-cell/home
投稿链接：https://www.editorialmanager.com/cancer-cell/default.aspx
本期文章：《癌细胞》：Online/在线发表
