title: Enterococcus hirae and Barnesiella intestinihominis Facilitate Cyclophosphamide-Induced Therapeutic Immunomodulatory Effects.
abstract: The efficacy of the anti-cancer immunomodulatory agent cyclophosphamide (CTX) relies on intestinal bacteria. How and which relevant bacterial species are involved in tumor immunosurveillance, and their mechanism of action are unclear. Here, we identified two bacterial species, Enterococcus hirae and Barnesiella intestinihominis that are involved during CTX therapy. Whereas E. hirae translocated from the small intestine to secondary lymphoid organs and increased the intratumoral CD8/Treg ratio, B. intestinihominis accumulated in the colon and promoted the infiltration of IFN-γ-producing γδT cells in cancer lesions. The immune sensor, NOD2, limited CTX-induced cancer immunosurveillance and the bioactivity of these microbes. Finally, E. hirae and B. intestinihominis specific-memory Th1 cell immune responses selectively predicted longer progression-free survival in advanced lung and ovarian cancer patients treated with chemo-immunotherapy. Altogether, E. hirae and B. intestinihominis represent valuable "oncomicrobiotics" ameliorating the efficacy of the most common alkylating immunomodulatory compound.
authors.affiliation: Institut de Cancérologie Gustave Roussy Cancer Campus (GRCC), 114 rue Edouard Vaillant, Villejuif, 94805, France; Institut National de la Santé Et de la Recherche Medicale (INSERM), U1015, GRCC, Villejuif, 94805, France; University of Paris-Saclay, Kremlin Bicêtre, 94270, France.
authors.forename: Romain
authors.initials: R
authors.lastname: Daillère
authors.affiliation: Institut de Cancérologie Gustave Roussy Cancer Campus (GRCC), 114 rue Edouard Vaillant, Villejuif, 94805, France; Institut National de la Santé Et de la Recherche Medicale (INSERM), U1015, GRCC, Villejuif, 94805, France; University of Paris-Saclay, Kremlin Bicêtre, 94270, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Vétizou
authors.affiliation: University Lille, CNRS, Inserm, CHRU Lille, Institut Pasteur de Lille, U1019-UMR 8204-CIIL, Centre d'Infection et d'Immunité de Lille, 59000 Lille, France.
authors.forename: Nadine
authors.initials: N
authors.lastname: Waldschmitt
authors.affiliation: Institut de Cancérologie Gustave Roussy Cancer Campus (GRCC), 114 rue Edouard Vaillant, Villejuif, 94805, France; Institut National de la Santé Et de la Recherche Medicale (INSERM), U1015, GRCC, Villejuif, 94805, France.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Yamazaki
authors.affiliation: Université de Caen Basse-Normandie, EA4655 U2RM (Équipe Antibio-Résistance), Caen, 14033, France; CHU de Caen, Service de Microbiologie, Caen, 14033, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Isnard
authors.affiliation: Institut de Cancérologie Gustave Roussy Cancer Campus (GRCC), 114 rue Edouard Vaillant, Villejuif, 94805, France; Institut National de la Santé Et de la Recherche Medicale (INSERM), U1015, GRCC, Villejuif, 94805, France; University of Paris-Saclay, Kremlin Bicêtre, 94270, France.
authors.forename: Vichnou
authors.initials: V
authors.lastname: Poirier-Colame
authors.affiliation: Institut de Cancérologie Gustave Roussy Cancer Campus (GRCC), 114 rue Edouard Vaillant, Villejuif, 94805, France; Institut National de la Santé Et de la Recherche Medicale (INSERM), U1015, GRCC, Villejuif, 94805, France; Center of Clinical Investigations in Biotherapies of Cancer (CICBT) 1428, Villejuif, 94805, France.
authors.forename: Connie P M
authors.initials: CPM
authors.lastname: Duong
authors.affiliation: Institut de Cancérologie Gustave Roussy Cancer Campus (GRCC), 114 rue Edouard Vaillant, Villejuif, 94805, France; Institut National de la Santé Et de la Recherche Medicale (INSERM), U1015, GRCC, Villejuif, 94805, France; Center of Clinical Investigations in Biotherapies of Cancer (CICBT) 1428, Villejuif, 94805, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Flament
authors.affiliation: Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, 78350 Jouy-en-Josas, France.
authors.forename: Patricia
authors.initials: P
authors.lastname: Lepage
authors.affiliation: Institut de Cancérologie Gustave Roussy Cancer Campus (GRCC), 114 rue Edouard Vaillant, Villejuif, 94805, France; Institut National de la Santé Et de la Recherche Medicale (INSERM), U1015, GRCC, Villejuif, 94805, France; Center of Clinical Investigations in Biotherapies of Cancer (CICBT) 1428, Villejuif, 94805, France.
authors.forename: Maria Paula
authors.initials: MP
authors.lastname: Roberti
authors.affiliation: Institut de Cancérologie Gustave Roussy Cancer Campus (GRCC), 114 rue Edouard Vaillant, Villejuif, 94805, France; Institut National de la Santé Et de la Recherche Medicale (INSERM), U1015, GRCC, Villejuif, 94805, France; University of Paris-Saclay, Kremlin Bicêtre, 94270, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Routy
authors.affiliation: Institut de Cancérologie Gustave Roussy Cancer Campus (GRCC), 114 rue Edouard Vaillant, Villejuif, 94805, France; Institut National de la Santé Et de la Recherche Medicale (INSERM), U1015, GRCC, Villejuif, 94805, France; University of Paris-Saclay, Kremlin Bicêtre, 94270, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Jacquelot
authors.affiliation: Lipids, Nutrition, Cancer, INSERM, U866, Dijon, 21078, France; Department of Medicine, Université de Bourgogne Franche-Comté, Dijon, 21078, France; Department of Oncology, Centre Georges François Leclerc, Dijon, 21000, France.
authors.forename: Lionel
authors.initials: L
authors.lastname: Apetoh
authors.affiliation: Institut de Cancérologie Gustave Roussy Cancer Campus (GRCC), 114 rue Edouard Vaillant, Villejuif, 94805, France; Institut National de la Santé Et de la Recherche Medicale (INSERM), U1015, GRCC, Villejuif, 94805, France; Center of Clinical Investigations in Biotherapies of Cancer (CICBT) 1428, Villejuif, 94805, France.
authors.forename: Sonia
authors.initials: S
authors.lastname: Becharef
authors.affiliation: Institut de Cancérologie Gustave Roussy Cancer Campus (GRCC), 114 rue Edouard Vaillant, Villejuif, 94805, France; Institut National de la Santé Et de la Recherche Medicale (INSERM), U1015, GRCC, Villejuif, 94805, France; Center of Clinical Investigations in Biotherapies of Cancer (CICBT) 1428, Villejuif, 94805, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Rusakiewicz
authors.affiliation: Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, 78350 Jouy-en-Josas, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Langella
authors.affiliation: Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, 78350 Jouy-en-Josas, France; AVENIR Team Gut Microbiota and Immunity, ERL, INSERM U 1157/UMR 7203, Faculté de Médecine, Saint-Antoine, Université Pierre et Marie Curie (UPMC), Paris, 75012, France; Service de Gastroentérologie, Hôpital Saint-Antoine, Assistance Publique-Hôpitaux de Paris (APHP), Paris, 75012, France.
authors.forename: Harry
authors.initials: H
authors.lastname: Sokol
authors.affiliation: INSERM U848, 94805 Villejuif, France; Metabolomics Platform, Institut Gustave Roussy, Villejuif, 94805, France; Equipe 11 labellisée Ligue contre le Cancer, Centre de Recherche des Cordeliers, INSERM U 1138, Paris, 75006, France; Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, 75015, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, 75006, France; Karolinska Institute, Department of Women's and Children's Health, Karolinska University Hospital, Stockholm, 17176, Sweden.
authors.forename: Guido
authors.initials: G
authors.lastname: Kroemer
authors.affiliation: Institut de Cancérologie Gustave Roussy Cancer Campus (GRCC), 114 rue Edouard Vaillant, Villejuif, 94805, France; Metabolomics Platform, Institut Gustave Roussy, Villejuif, 94805, France.
authors.forename: David
authors.initials: D
authors.lastname: Enot
authors.affiliation: Institut de Cancérologie Gustave Roussy Cancer Campus (GRCC), 114 rue Edouard Vaillant, Villejuif, 94805, France; Institut National de la Santé Et de la Recherche Medicale (INSERM), U1015, GRCC, Villejuif, 94805, France; University of Paris-Saclay, Kremlin Bicêtre, 94270, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, 75006, France.
authors.forename: Antoine
authors.initials: A
authors.lastname: Roux
authors.affiliation: Institut de Cancérologie Gustave Roussy Cancer Campus (GRCC), 114 rue Edouard Vaillant, Villejuif, 94805, France; University of Paris-Saclay, Kremlin Bicêtre, 94270, France.
authors.forename: Alexander
authors.initials: A
authors.lastname: Eggermont
authors.affiliation: INSERM U970, Paris Cardiovascular Research Center, Université Paris-Descartes, Sorbonne Paris Cité, Paris, 75015, France; Service d'immunologie biologique, Hôpital Européen Georges Pompidou, Paris, 75015 France.
authors.forename: Eric
authors.initials: E
authors.lastname: Tartour
authors.affiliation: INSERM U1143, 75005 Paris, France; Institut Curie, PSL Research University, Endocytic Trafficking and Therapeutic Delivery group, Paris, 75248, France; CNRS UMR 3666, Paris, 75005, France.
authors.forename: Ludger
authors.initials: L
authors.lastname: Johannes
authors.affiliation: Service de microbiologie, GRCC, Villejuif, 94805, France.
authors.forename: Paul-Louis
authors.initials: PL
authors.lastname: Woerther
authors.affiliation: Service de microbiologie, GRCC, Villejuif, 94805, France.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Chachaty
authors.affiliation: Institut de Cancérologie Gustave Roussy Cancer Campus (GRCC), 114 rue Edouard Vaillant, Villejuif, 94805, France; University of Paris-Saclay, Kremlin Bicêtre, 94270, France.
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Soria
authors.affiliation: Department of Radiation Oncology, Weill Cornell Medicine, New York, NY, USA.
authors.forename: Encouse
authors.initials: E
authors.lastname: Golden
authors.affiliation: Department of Radiation Oncology, Weill Cornell Medicine, New York, NY, USA.
authors.forename: Silvia
authors.initials: S
authors.lastname: Formenti
authors.affiliation: Department of Immunology and Pathology, Monash University, Alfred Hospital Precinct, Melbourne, Prahran, Victoria 3181, Australia.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Plebanski
authors.affiliation: Department of Immunology and Pathology, Monash University, Alfred Hospital Precinct, Melbourne, Prahran, Victoria 3181, Australia.
authors.forename: Mutsa
authors.initials: M
authors.lastname: Madondo
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany.
authors.forename: Philip
authors.initials: P
authors.lastname: Rosenstiel
authors.affiliation: AIX MARSEILLE UNIVERSITE, URMITE (Unité de Recherche sur les Maladies Infectieuses et Tropicales Emergentes), UMR 7278, INSERM 1095, IRD 198, Faculté de Médecine, Marseille 13005, France.
authors.forename: Didier
authors.initials: D
authors.lastname: Raoult
authors.affiliation: Université de Caen Basse-Normandie, EA4655 U2RM (Équipe Antibio-Résistance), Caen, 14033, France; CHU de Caen, Service de Microbiologie, Caen, 14033, France; CNR de la Résistance aux Antibiotiques, Laboratoire Associé Entérocoques, Caen, 14033, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Cattoir
authors.affiliation: Institut Pasteur, Unit Biology and Genetics of the bacterial Cell Wall, Paris, 75015, France.
authors.forename: Ivo Gomperts
authors.initials: IG
authors.lastname: Boneca
authors.affiliation: University Lille, CNRS, Inserm, CHRU Lille, Institut Pasteur de Lille, U1019-UMR 8204-CIIL, Centre d'Infection et d'Immunité de Lille, 59000 Lille, France.
authors.forename: Mathias
authors.initials: M
authors.lastname: Chamaillard
authors.affiliation: Institut de Cancérologie Gustave Roussy Cancer Campus (GRCC), 114 rue Edouard Vaillant, Villejuif, 94805, France; Institut National de la Santé Et de la Recherche Medicale (INSERM), U1015, GRCC, Villejuif, 94805, France; University of Paris-Saclay, Kremlin Bicêtre, 94270, France; Center of Clinical Investigations in Biotherapies of Cancer (CICBT) 1428, Villejuif, 94805, France. Electronic address: laurence.zitvogel@gustaveroussy.fr.
authors.forename: Laurence
authors.initials: L
authors.lastname: Zitvogel
mesh_terms: D000818:Animals; D003106:Colon / Q000276:immunology / Q000382:microbiology; D003520:Cyclophosphamide / Q000494:pharmacology*; D000070076:Enterococcus hirae / Q000276:immunology*; D007155:Immunologic Factors / Q000276:immunology*; D007156:Immunologic Memory / Q000276:immunology; D007167:Immunotherapy / Q000379:methods; D007371:Interferon-gamma / Q000276:immunology; D007421:Intestine, Small / Q000276:immunology / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D015166:Monitoring, Immunologic; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology*; D053473:Nod2 Signaling Adaptor Protein / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology
chemical_list: D007155:Immunologic Factors; D053473:Nod2 Signaling Adaptor Protein; D007371:Interferon-gamma; D003520:Cyclophosphamide