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

Maria Paula Roberti (1, 2, 3) , Satoru Yonekura (1, 2, 4) , Connie P. M. Duong (1, 2) , Marion Picard (1, 2, 5) , Gladys Ferrere (1, 2) , Maryam Tidjani Alou (1, 2) , Conrad Rauber (1, 2, 4) , Valerio Iebba (1, 2) , Christian H. K. Lehmann (6) , Lukas Amon (6) , Diana Dudziak (6) , Lisa Derosa (1, 2, 3) , Bertrand Routy (1, 2, 4) , Caroline Flament (1, 2, 3) , Corentin Richard (7) , Romain Daillère (1, 2) , Aurélie Fluckiger (1, 2) , Isabelle van Seuningen (8, 9) , Mathias Chamaillard (10) , Audrey Vincent (8, 9) , Stephanie Kourula (11, 12) , Paule Opolon (1) , Pierre Ly (1, 2) , Eugénie Pizzato (1, 2) , Sonia Becharef (1, 2) , Juliette Paillet (4, 13, 1) , Christophe Klein (13) , Florence Marliot (13) , Filippo Pietrantonio (14, 15) , Stéphane Benoist (16) , Jean-Yves Scoazec (1) , Peggy Dartigues (1) , Antoine Hollebecque (1) , David Malka (1) , Franck Pagès (13) , Jérôme Galon (13) , Ivo Gomperts Boneca (5, 17) , Patricia Lepage (18) , Bernhard Ryffel (19) , Didier Raoult (20) , Alexander Eggermont (1, 2) , Tom Vanden Berghe (11, 12) , François Ghiringhelli (7) , Peter Vandenabeele (11, 12) , Guido Kroemer (13, 1, 21, 22) , Laurence Zitvogel (1, 2, 3, 4)

1 Cancer Campus
2 ITIC - Immunologie anti-tumorale et immunothérapie des cancers
3 CIC 1428 , CBT 507 - Centre d'Investigation Clinique en Biotherapie des cancers
4 Université Paris-Saclay
5 BGPB - Biologie et Génétique de la Paroi bactérienne - Biology and Genetics of Bacterial Cell Wall
6 FAU - Friedrich-Alexander Universität Erlangen-Nürnberg = University of Erlangen-Nuremberg
7 UNICANCER/CRLCC-CGFL - Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon]
8 JPArc - Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837
9 CANTHER - Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277
10 PHYCELL - Laboratoire de Physiologie Cellulaire : Canaux ioniques, inflammation et cancer - U 1003
11 IRC - VIB-UGent Center for Inflammation Research [Gand, Belgique]
12 UGENT - Universiteit Gent = Ghent University
13 CRC (UMR_S_1138 / U1138) - Centre de Recherche des Cordeliers
14 IRCCS Istituto Nazionale dei Tumori [Milano]
15 UNIMI - Università degli Studi di Milano = University of Milan
16 Hôpital Bicêtre [AP-HP, Le Kremlin-Bicêtre]
17 INSERM - Institut National de la Santé et de la Recherche Médicale
18 MICALIS - MICrobiologie de l'ALImentation au Service de la Santé
19 INEM - Immunologie et Neurogénétique Expérimentales et Moléculaires
20 INMED - INSERM U1249 - Institut de Neurobiologie de la Méditerranée [Aix-Marseille Université]
21 HEGP - Hôpital Européen Georges Pompidou [APHP]
22 Karolinska University Hospital [Stockholm]

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.

Mots clés: proximal colon; cancer; apoptosis; prognosis

Domaines: Sciences du Vivant [q-bio]

Maria Paula Roberti, Satoru Yonekura, Connie P. M. Duong, Marion Picard, Gladys Ferrere, et al.. Chemotherapy-induced ileal crypt apoptosis and the ileal microbiome shape immunosurveillance and prognosis of proximal colon cancer. Nature Medicine, 2020, 26 (6), p. 919-931. ⟨10.1038/s41591-020-0882-8⟩. ⟨hal-03313676⟩