Intestinal inhibition of Atg7 prevents tumour initiation through a microbiome-influenced immune response and suppresses tumour growth
Jonathan Levy
(1)
,
Walfran Cacheux
(2, 3, 4)
,
Medhi Ait Bara
(1)
,
Antoine L'Hermitte
(1)
,
Patricia Lepage
(5)
,
Marie Fraudeau
(1)
,
Coralie Trentesaux
(1)
,
Julie Lemarchand
(1)
,
Aurélie Durand
(1)
,
Anne-Marie Crain
(6, 1)
,
Carmen Marchiol
(1)
,
Gilles Renault
(7)
,
Florent Dumont
(1)
,
Franck Letourneur
(1)
,
Myriam Delacres
(8)
,
Alain Schmitt
(1)
,
Benoît Terris
(7, 9)
,
Christine Perret
(1)
,
Mathias Chamaillard
(8)
,
Jean-Pierre Couty
(6, 1)
,
Béatrice Romagnolo
(1)
1
IC UM3 (UMR 8104 / U1016) -
Institut Cochin
2 UMR_S567 / UMR 8104 - Institut Cochin
3 Département d'Oncologie Médicale
4 Institut Curie [Paris]
5 MICALIS - MICrobiologie de l'ALImentation au Service de la Santé
6 UPD7 UFR Sciences du Vivant - Université Paris Diderot - Paris 7 - UFR Sciences du Vivant
7 UPD5 - Université Paris Descartes - Paris 5
8 CIIL - Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204
9 AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris]
2 UMR_S567 / UMR 8104 - Institut Cochin
3 Département d'Oncologie Médicale
4 Institut Curie [Paris]
5 MICALIS - MICrobiologie de l'ALImentation au Service de la Santé
6 UPD7 UFR Sciences du Vivant - Université Paris Diderot - Paris 7 - UFR Sciences du Vivant
7 UPD5 - Université Paris Descartes - Paris 5
8 CIIL - Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204
9 AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris]
Walfran Cacheux
- Fonction : Auteur
Patricia Lepage
- Fonction : Auteur
- PersonId : 748833
- IdHAL : patricia-lepage
- ORCID : 0000-0002-9501-6771
- IdRef : 096241063
Florent Dumont
- Fonction : Auteur
- PersonId : 1342273
- IdHAL : fdumbioinfo
- ORCID : 0000-0002-4439-5070
Mathias Chamaillard
- Fonction : co dernier-auteur
Jean-Pierre Couty
- Fonction : co dernier-auteur
Résumé
Here, we show that autophagy is activated in the intestinal epithelium in murine and human colorectal cancer and that the conditional inactivation of Atg7 in intestinal epithelial cells inhibits the formation of pre-cancerous lesions in Apc(+/-) mice by enhancing anti-tumour responses. The antibody-mediated depletion of CD8(+) T cells showed that these cells are essential for the anti-tumoral responses mediated by the inhibition of autophagy. We show that Atg7 deficiency leads to intestinal dysbiosis and that the microbiota is required for anticancer responses. In addition, Atg7 deficiency resulted in a stress response accompanied by metabolic defects, AMPK activation and p53-mediated cell-cycle arrest in tumour cells but not in normal tissue. This study reveals that the inhibition of autophagy within the epithelium may prevent the development and progression of colorectal cancer in genetically predisposed patients.