于君团队:靶向METTL3,或能增强大肠癌免疫治疗
创作:mildbreeze 审核:mildbreeze 07月01日
  • METTL3(催化RNA的m6A甲基化修饰的关键酶)可促进小鼠结直肠癌(CRC);
  • 多个小鼠模型中,敲除CRC细胞的METTL3可减少髓系抑制细胞(MDSC)积累,促进CD4和CD8 T细胞的持续活化和增殖,从而增强抗肿瘤免疫,抑制CRC;
  • METTL3通过促进转录因子BHLHE41的m6A甲基化,驱动CRC细胞表达促炎细胞因子CXCL1,进而通过作用于MDSC表面受体CXCR2来促进其迁移和招募;
  • 用sgRNA靶向METTL3或用METTL3抑制剂STM2457,可增强抗PD1对小鼠CRC的疗效。
主编推荐语
mildbreeze
m6A甲基化是最普遍的RNA修饰,也是结直肠癌(CRC)中的重要表观转录组学机制。香港中文大学于君团队在Gastroenterology发表最新研究,通过多个小鼠模型,揭示了METTL3(催化RNA的m6A甲基化修饰的关键酶)在促进CRC免疫抑制微环境中的作用,表明METTL3通过m6A-BHLHE41-CXCL1/CXCR2轴促进髓系抑制细胞的积累,从而促进CRC生长。该研究进一步显示,靶向METTL3或是增强大肠癌免疫治疗的新思路。
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Gastroenterology [IF:33.883]

METTL3 inhibits anti-tumor immunity by targeting m6A-BHLHE41-CXCL1/CXCR2 axis to promote colorectal cancer

METTL3通过靶向m6A-BHLHE41-CXCL1/CXCR2轴抑制抗肿瘤免疫,以促进结直肠癌

10.1053/j.gastro.2022.06.024

06-11, Article

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Background & Aims: N6-Methyladenosine (m6A) is the most prevalent RNA modification and recognized as an important epitranscriptomic mechanism in colorectal cancer (CRC). We aim to exploit whether and how tumor-intrinsic m6A modification drove by methyltransferase like 3 (METTL3) can dictate the immune landscape of CRC.
Methods: Mettl3 knockout mice, CD34+ humanized mice and different syngeneic mice models were employed. Immune cells composition and cytokines level were analyzed by flow cytometry and Cytokine 23-Plex immunoassay, respectively. M6A-seq and RNA-seq were performed to identify downstream targets and pathways of METTL3. Human CRC specimens (n=176) were used to evaluate correlation between METTL3 expression and myeloid-derived suppressor cells (MDSCs) infiltration.
Results: We demonstrated that silencing of METTL3 in CRC cells reduced MDSCs accumulation to sustain activation and proliferation of CD4+ and CD8+ T cell, and eventually suppressed CRC in ApcMin/+Mettl3+/- mice, CD34+ humanized mice and syngeneic mice models. Mechanistically, METTL3 activated m6A-BHLHE41-CXCL1 axis by analysis of m6A-seq, RNA-seq and cytokines arrays. METTL3 promoted BHLHE41 expression in m6A-dependent manner, which subsequently induced CXCL1 transcription to enhance MDSC migration in vitro. However, the effect was negligible upon BHLHE41 depletion, CXCL1 protein or CXCR2 inhibitor SB265610 administration, inferring that METTL3 promotes MDSC migration via BHLHE41-CXCL1/CXCR2. Consistently, depletion of MDSCs by anti-Gr1 antibody or SB265610 blocked tumor-promoting effect of METTL3 in vivo. Importantly, targeting METTL3 by METTL3-sgRNA or specific inhibitor potentiated the effect of anti-PD1 treatment.
Conclusions: Our study identifies METTL3 as a potential therapeutic target for CRC immunotherapy whose inhibition reverses immune suppression through m6A-BHLHE41-CXCL1 axis. METTL3 inhibition plus anti-PD-1 treatment show promising antitumor efficacy against CRC.

First Authors:
Huarong Chen

Correspondence Authors:
Jun Yu

All Authors:
Huarong Chen,Yasi Pan,Qiming Zhou,Cong Liang,Chi Chun Wong,Yunfei Zhou,Dan Huang,Weixin Liu,Jianning Zhai,Hongyan Gou,Hao Su,Xiaoting Zhang,HongZhi Xu,Yifei Wang,Wei Kang,William Ka Kei Wu,Jun Yu

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