1. Chemotherapy-induced ileal crypt apoptosis and the ileal microbiome shape immunosurveillance and prognosis of proximal colon cancer.
- Author
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Roberti MP, Yonekura S, Duong CPM, Picard M, Ferrere G, Tidjani Alou M, Rauber C, Iebba V, Lehmann CHK, Amon L, Dudziak D, Derosa L, Routy B, Flament C, Richard C, Daillère R, Fluckiger A, Van Seuningen I, Chamaillard M, Vincent A, Kourula S, Opolon P, Ly P, Pizzato E, Becharef S, Paillet J, Klein C, Marliot F, Pietrantonio F, Benoist S, Scoazec JY, Dartigues P, Hollebecque A, Malka D, Pagès F, Galon J, Gomperts Boneca I, Lepage P, Ryffel B, Raoult D, Eggermont A, Vanden Berghe T, Ghiringhelli F, Vandenabeele P, Kroemer G, and Zitvogel L
- Subjects
- Adenocarcinoma immunology, Adenocarcinoma microbiology, Adenocarcinoma pathology, Adult, Aged, Aged, 80 and over, Animals, Antineoplastic Agents therapeutic use, Apoptosis immunology, Bacteroides fragilis, Cell Line, Tumor, Colonic Neoplasms immunology, Colonic Neoplasms microbiology, Colonic Neoplasms pathology, Epithelial Cells drug effects, Epithelial Cells immunology, Epithelial Cells pathology, Female, Firmicutes, Gastrointestinal Microbiome physiology, Humans, Ileum immunology, Ileum microbiology, Ileum pathology, Immunogenic Cell Death drug effects, Immunogenic Cell Death immunology, Immunologic Surveillance drug effects, Immunologic Surveillance immunology, Interleukin-12 immunology, Intestinal Mucosa, Lymphocytes, Tumor-Infiltrating immunology, Male, Mice, Middle Aged, Oxaliplatin therapeutic use, Prognosis, Programmed Cell Death 1 Receptor antagonists & inhibitors, Receptors, Interleukin-1 Type I immunology, T-Lymphocytes, Helper-Inducer drug effects, T-Lymphocytes, Helper-Inducer immunology, Adenocarcinoma drug therapy, Antineoplastic Agents pharmacology, Apoptosis drug effects, Colonic Neoplasms drug therapy, Gastrointestinal Microbiome immunology, Ileum drug effects, Lymphocytes, Tumor-Infiltrating drug effects, Oxaliplatin pharmacology
- Abstract
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 TFH 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 TFH 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+ TFH 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.- Published
- 2020
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