Chemotherapy-induced ileal crypt apoptosis and the ileal microbiome shape immunosurveillance and prognosis of proximal colon cancer
Chemotherapy-induced ileal crypt apoptosis and the ileal microbiome shape immunosurveillance and prognosis of proximal colon cancer
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DOI：
10.1038/s41591-020-0882-8
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发表时间：
2020-05-25
期刊：
影响因子：
82.9
通讯作者：
Zitvogel, Laurence
中科院分区：
文献类型：
--
作者：
Roberti, Maria Paula;Yonekura, Satoru;Zitvogel, Laurence
结肠癌的预后取决于肿瘤浸润性淋巴细胞，包括滤泡辅助性T细胞(T-FH)和化疗诱导的免疫反应的疗效。目前尚不清楚肠道微生物是否有助于激发T-FH细胞驱动的反应。在这里，我们表明，回肠微生物区系决定了回肠上皮细胞(IECS)耐受性和免疫性细胞死亡，以及CC患者和小鼠T-FH细胞的积累。抑制IEC的凋亡导致化疗诱导的小鼠对CC的免疫监视功能受损。对CC的保护性免疫反应与脆弱类杆菌和白藜芦科细菌在回肠的滞留有关。在这些共生体存在的情况下，凋亡的回肠IECs以白介素1R1和白介素12依赖的方式诱导PD-1(+)T-FH细胞。回肠微生物群独立于微卫星不稳定性决定了CC化疗和PD-1阻断的疗效。这些结果表明，免疫原性回肠细胞凋亡与化疗后CC的预后有关。局部微生物群通过调节耐受性与免疫性回肠上皮细胞死亡，进而影响滤泡辅助T细胞的启动，从而影响结肠癌的化疗疗效。
The prognosis of colon cancer (CC) is dictated by tumor-infiltrating lymphocytes, including follicular helper T (T-FH) cells and the efficacy of chemotherapy-induced immune responses. It remains unclear whether gut microbes contribute to the elicitation of T-FH cell-driven responses. Here, we show that the ileal microbiota dictates tolerogenic versus immunogenic cell death of ileal intestinal epithelial cells (IECs) and the accumulation of T-FH cells in patients with CC and mice. Suppression of IEC apoptosis led to compromised chemotherapy-induced immunosurveillance against CC in mice. Protective immune responses against CC were associated with residence of Bacteroides fragilis and Erysipelotrichaceae in the ileum. In the presence of these commensals, apoptotic ileal IECs elicited PD-1(+) T-FH cells in an interleukin-1R1- and interleukin-12-dependent manner. The ileal microbiome governed the efficacy of chemotherapy and PD-1 blockade in CC independently of microsatellite instability. These findings demonstrate that immunogenic ileal apoptosis contributes to the prognosis of chemotherapy-treated CC.Local microbiome composition influences treatment efficacy of chemotherapy in colon cancer via modulation of tolerogenic versus immunogenic ileal intestinal epithelial cell death, which in turn influences follicular helper T cell priming.