Chemotherapy-induced ileal crypt apoptosis and the ileal microbiome shape immunosurveillance and prognosis of proximal colon cancer.

Maria Paula Roberti, Satoru Yonekura, Connie P. M. Duong, Marion Picard, Gladys Ferrere, Maryam Tidjani Alou, Conrad Rauber, Valerio Iebba, Christian H. K. Lehmann, Lukas Amon, Diana Dudziak, Lisa Derosa, Bertrand Routy, Caroline Flament, Corentin Richard, Romain Daillère, Aurélie Fluckiger, Isabelle Van Seuningen, Mathias Chamaillard, Audrey VincentStephanie Kourula, Paule Opolon, Pierre Ly, Eugénie Pizzato, Sonia Becharef, Juliette Paillet, Christophe Klein, Florence Marliot, Filippo Pietrantonio, Stéphane Benoist, Jean-Yves Scoazec, Peggy Dartigues, Antoine Hollebecque, David Malka, Franck Pagès, Jérôme Galon, Ivo Gomperts Boneca, Patricia Lepage, Bernard Ryffel, Didier Raoult, Alexander Eggermont, Tom Vanden Berghe, François Ghiringhelli, Peter Vandenabeele, Guido Kroemer, Laurence Zitvogel

Research output: Contribution to journalArticlepeer-review

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 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.
Original languageEnglish
JournalNature Medicine
Issue number6
Publication statusPublished - Jun 1 2020

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