Microbiota triggers STING-type I IFN-dependent monocyte reprogramming of the tumor microenvironment.
Microbiota triggers STING-type I IFN-dependent monocyte reprogramming of the tumor microenvironment.
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DOI：
10.1016/j.cell.2021.09.019
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发表时间：
2021-10-14
期刊：
影响因子：
64.5
通讯作者：
Goldszmid RS
中科院分区：
文献类型：
--
作者：
Lam KC;Araya RE;Huang A;Chen Q;Di Modica M;Rodrigues RR;Lopès A;Johnson SB;Schwarz B;Bohrnsen E;Cogdill AP;Bosio CM;Wargo JA;Lee MP;Goldszmid RS
肿瘤微环境（TME）影响癌症进展和治疗反应。因此，了解是什么调节TME免疫区室是至关重要的。在这里，我们表明，微生物群信号程序单核吞噬细胞在TME对免疫刺激单核细胞和树突状细胞（DC）。单细胞RNA测序显示，微生物群的缺乏使TME偏向促肿瘤发生的巨噬细胞。从机制上讲，我们表明微生物来源的STING激动剂诱导肿瘤内单核细胞产生I型IFN（IFN-I），以调节巨噬细胞极化和NK-DC串扰。用高纤维饮食调节微生物群触发了肿瘤内IFN-I-NK-DC轴并提高了免疫检查点阻断（ICB）的功效。我们在用ICB治疗的黑色素瘤患者中验证了我们的发现，并表明预测的肿瘤内IFN-I和应答者与非应答者患者之间的免疫组成差异可以通过粪便微生物群移植转移。我们的研究揭示了微生物群和先天TME之间的机械联系，可以利用它来改善癌症治疗。肠道微生物群通过STING I型IFN依赖性机制调节肿瘤微环境的促/抗肿瘤平衡。喂食高纤维饮食或转移免疫检查点阻断（ICB）应答者黑色素瘤患者的粪便微生物群触发了这一途径，并对肿瘤内单核吞噬细胞进行编程，以促进抗癌免疫和ICB疗效。
The tumor microenvironment (TME) influences cancer progression and therapy response. Therefore, understanding what regulates the TME immune compartment is vital. Here, we show that microbiota signals program mononuclear phagocytes in the TME towards immunostimulatory monocytes and dendritic cells (DCs). Single-cell RNA sequencing revealed that absence of microbiota skews the TME towards pro-tumorigenic macrophages. Mechanistically, we show that microbiota-derived STING agonists induce type I IFN (IFN-I) production by intratumoral monocytes to regulate macrophage polarization and NK–DC crosstalk. Microbiota modulation with high-fiber diet triggered the intratumoral IFN-I–NK–DC axis and improved efficacy of immune checkpoint blockade (ICB). We validated our findings in melanoma patients treated with ICB and showed that the predicted intratumoral IFN-I and immune compositional differences between responder and non-responder patients can be transferred by fecal microbiota transplantation. Our study uncovers a mechanistic link between microbiota and the innate TME that can be harnessed to improve cancer therapies. Gut microbiota tunes the pro/anti-tumorigenic balance of the tumor microenvironment via STING-type I IFN-dependent mechanism. Feeding high-fiber diet or transferring fecal microbiota from immune checkpoint blockade (ICB) responder melanoma patients triggers this pathway and programs intratumoral mononuclear phagocytes to promote anticancer immunity and ICB efficacy.
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影响因子：
4.3
作者：
Chen H;Lau MC;Wong MT;Newell EW;Poidinger M;Chen J
通讯作者：
Chen J
影响因子：
48
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影响因子：
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Young, Howard A.
影响因子：
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作者：
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Schreiber, RD
影响因子：
50.5
作者：
Chalabi, M.;Cardona, A.;Herrera, F. G.
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