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 Vincent; Stephanie 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

doi:10.1038/s41591-020-0882-8

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 journal › Article › peer-review

141 Citations (Scopus)

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 language	English
Pages (from-to)	919-931
Number of pages	13
Journal	Nature Medicine
Volume	26
Issue number	6
DOIs	https://doi.org/10.1038/s41591-020-0882-8
Publication status	Published - 1 Jun 2020
Externally published	Yes

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Roberti, M. P., Yonekura, S., Duong, C. P. M., Picard, M., Ferrere, G., Tidjani Alou, M., Rauber, C., Iebba, V., Lehmann, C. H. K., Amon, L., Dudziak, D., Derosa, L., Routy, B., Flament, C., Richard, C., Daillère, R., Fluckiger, A., Van Seuningen, I., Chamaillard, M., ... Zitvogel, L. (2020). Chemotherapy-induced ileal crypt apoptosis and the ileal microbiome shape immunosurveillance and prognosis of proximal colon cancer. Nature Medicine, 26(6), 919-931. https://doi.org/10.1038/s41591-020-0882-8

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title = "Chemotherapy-induced ileal crypt apoptosis and the ileal microbiome shape immunosurveillance and prognosis of proximal colon cancer",

abstract = "The prognosis of colon cancer (CC) is dictated by tumor-infiltrating lymphocytes, including follicular helper T (TFH) 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.",

author = "Roberti, {Maria Paula} and Satoru Yonekura and Duong, {Connie P.M.} and Marion Picard and Gladys Ferrere and {Tidjani Alou}, Maryam and Conrad Rauber and Valerio Iebba and Lehmann, {Christian H.K.} and Lukas Amon and Diana Dudziak and Lisa Derosa and Bertrand Routy and Caroline Flament and Corentin Richard and Romain Daill{\`e}re and Aur{\'e}lie Fluckiger and {Van Seuningen}, Isabelle and Mathias Chamaillard and Audrey Vincent and Stephanie Kourula and Paule Opolon and Pierre Ly and Eug{\'e}nie Pizzato and Sonia Becharef and Juliette Paillet and Christophe Klein and Florence Marliot and Filippo Pietrantonio and St{\'e}phane Benoist and Scoazec, {Jean Yves} and Peggy Dartigues and Antoine Hollebecque and David Malka and Franck Pag{\`e}s and J{\'e}r{\^o}me Galon and {Gomperts Boneca}, Ivo and Patricia Lepage and Bernard Ryffel and Didier Raoult and Alexander Eggermont and {Vanden Berghe}, Tom and Fran{\c c}ois Ghiringhelli and Peter Vandenabeele and Guido Kroemer and Laurence Zitvogel",

note = "Publisher Copyright: {\textcopyright} 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2020",

month = jun,

day = "1",

doi = "10.1038/s41591-020-0882-8",

language = "English",

volume = "26",

pages = "919--931",

journal = "Nature Medicine",

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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 & Zitvogel, L 2020, 'Chemotherapy-induced ileal crypt apoptosis and the ileal microbiome shape immunosurveillance and prognosis of proximal colon cancer', Nature Medicine, vol. 26, no. 6, pp. 919-931. https://doi.org/10.1038/s41591-020-0882-8

TY - JOUR

T1 - Chemotherapy-induced ileal crypt apoptosis and the ileal microbiome shape immunosurveillance and prognosis of proximal colon cancer

AU - Roberti, Maria Paula

AU - Yonekura, Satoru

AU - Duong, Connie P.M.

AU - Picard, Marion

AU - Ferrere, Gladys

AU - Tidjani Alou, Maryam

AU - Rauber, Conrad

AU - Iebba, Valerio

AU - Lehmann, Christian H.K.

AU - Amon, Lukas

AU - Dudziak, Diana

AU - Derosa, Lisa

AU - Routy, Bertrand

AU - Flament, Caroline

AU - Richard, Corentin

AU - Daillère, Romain

AU - Fluckiger, Aurélie

AU - Van Seuningen, Isabelle

AU - Chamaillard, Mathias

AU - Vincent, Audrey

AU - Kourula, Stephanie

AU - Opolon, Paule

AU - Ly, Pierre

AU - Pizzato, Eugénie

AU - Becharef, Sonia

AU - Paillet, Juliette

AU - Klein, Christophe

AU - Marliot, Florence

AU - Pietrantonio, Filippo

AU - Benoist, Stéphane

AU - Scoazec, Jean Yves

AU - Dartigues, Peggy

AU - Hollebecque, Antoine

AU - Malka, David

AU - Pagès, Franck

AU - Galon, Jérôme

AU - Gomperts Boneca, Ivo

AU - Lepage, Patricia

AU - Ryffel, Bernard

AU - Raoult, Didier

AU - Eggermont, Alexander

AU - Vanden Berghe, Tom

AU - Ghiringhelli, François

AU - Vandenabeele, Peter

AU - Kroemer, Guido

AU - Zitvogel, Laurence

PY - 2020/6/1

Y1 - 2020/6/1

N2 - The prognosis of colon cancer (CC) is dictated by tumor-infiltrating lymphocytes, including follicular helper T (TFH) 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.

AB - The prognosis of colon cancer (CC) is dictated by tumor-infiltrating lymphocytes, including follicular helper T (TFH) 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.

UR - http://www.scopus.com/inward/record.url?scp=85085299090&partnerID=8YFLogxK

U2 - 10.1038/s41591-020-0882-8

DO - 10.1038/s41591-020-0882-8

M3 - Article

C2 - 32451498

AN - SCOPUS:85085299090

SN - 1078-8956

VL - 26

SP - 919

EP - 931

JO - Nature Medicine

JF - Nature Medicine

IS - 6

ER -

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

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