YTHDF2通过CD8+T细胞调控肿瘤相关巨噬细胞重编程并控制抗肿瘤免疫

SCI 23 February 2023

YTHDF2 orchestrates tumor-associated macrophage reprogramming and controls antitumor immunity through CD8+ T cells

（IF: Nat Immunol., 31.25）

Ma S, Sun B, Duan S, Han J, Barr T, Zhang J, Bissonnette MB, Kortylewski M, He C, Chen J, Caligiuri MA, Yu J. YTHDF2 orchestrates tumor-associated macrophage reprogramming and controls antitumor immunity through CD8+ T cells. Nat Immunol. 2023 Feb;24(2):255-266. 

Correspondence: mcaligiuri@coh.org; jiayu@coh.org

Despite tumor-associated macrophages (TAMs) playing a key role in shaping the tumor microenvironment (TME), the mechanisms by which TAMs influence the TME and contribute to cancer progression remain unclear. Here, we show that the N6-methyladenosine reader YTHDF2 regulates the antitumor functions of TAMs. YTHDF2 deficiency in TAMs suppressed tumor growth by reprogramming TAMs toward an antitumoral phenotype and increasing their antigen cross-presentation ability, which in turn enhanced CD8+ T cell-mediated antitumor immunity. YTHDF2 deficiency facilitated the reprogramming of TAMs by targeting interferon-γ−STAT1 signaling. The expression of YTHDF2 in TAMs was regulated by interleukin-10−STAT3 signaling. Selectively targeting YTHDF2 in TAMs using a Toll-like receptor 9 agonist-conjugated small interfering RNA reprogrammed TAMs toward an antitumoral phenotype, restrained tumor growth and enhanced the efficacy of PD-L1 antibody therapy. Collectively, our findings describe the role of YTHDF2 in orchestrating TAMs and suggest that YTHDF2 inhibition is an effective approach to enhance cancer immunotherapy.

虽然肿瘤相关巨噬细胞（TAMs）在形成肿瘤微环境（TME）中起着关键作用，但是TAMs影响TME并促进癌症进展的机制仍不清楚。此处，我们阐明了N6-甲基腺苷阅读器YTHDF2调节TAMs的抗肿瘤功能。TAMs中的YTHDF2缺陷通过将TAMs重编程为抗肿瘤表型并增加其抗原交叉呈递能力，来抑制肿瘤生长，这反过来又增强了CD8+T细胞介导的抗肿瘤免疫。YTHDF2缺陷通过靶向干扰素-γ−STAT1信号促进TAMs的重编程。TAMs中YTHDF2的表达受白介素-10−STAT3信号传导的调节。使用Toll样受体9激动剂缀合的小干扰RNA选择性靶向TAMs中的YTHDF2，将TAMs重编程为抗肿瘤表型，抑制肿瘤生长并增强PD-L1抗体治疗的功效。总之，我们的发现描述了YTHDF2在调节TAMs中的作用，并表明抑制YTHDF2是增强癌症免疫治疗的有效途径。

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