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Two species of bacteria present in the gut boost the efficacy of cyclophosphamide-based chemotherapies by optimising the antitumour immunity induced by this drug. This is reported by researchers from Inserm, Gustave Roussy, CNRS, Institut Pasteur Lille, and the Universities of Paris Sud and of Lille in an article published on 4 October in the journal Immunity.
Recent studies have shown that certain gut microbes encourage tumours to grow, whereas others contribute to making cancer treatments more effective. It remained necessary to identify the nature and mode of action of the bacterial species capable of optimising the antitumour response induced by chemotherapy.
In this new study, Mathias Chamaillard[1], Laurence Zitvogel[2] and their collaborators showed that two gut bacteria, Enterococcus hirae and Barnesiella intestinihominis, together potentiate the therapeutic effects of cyclophosphamide, a chemotherapeutic agent used to treat many cancers.
How? Chemotherapy has secondary effects that include increased permeability of the intestinal barrier and, consequently, the entry of the bacteria constituting the microbiota into the bloodstream. To combat this abnormal entry of bacteria into the bloodstream, an immune response is initiated. Against all expectations, this response is beneficial for patients, since it can also lead to the destruction of the tumour cells. The tumour is therefore attacked directly by cyclophosphamide and indirectly by this “booster” effect of the bacteria.
Several preclinical models enabled the researchers to demonstrate that the antitumour immune response induced by cyclophosphamide is optimised after oral administration of E. hirae. Treatment by oral administration of B. intestinihominis enabled a similar effect to be obtained.
The researchers then analysed the immune profile of the blood lymphocytes from 38 patients with advanced stage cancer of the lung or ovary, and treated by chemoimmunotherapy. They discovered that the presence of T memory lymphocytes specific for E. hirae and B. intestinihominis makes it possible to predict the period for which a patient lives with a cancer without it getting worse, during and after a treatment.
“The efficacy of a cancer drug relies on a complex interaction between the patient’s microbiome and his/her ability to mount an effective immune response against certain bacteria of the gut microbiota,” explains one of the main authors of the study, Mathias Chamaillard, Inserm Research Director.
“These results allow us to consider increasing the efficacy of these treatments by optimising the use of antibiotics, but also by supplementing the numbers of certain bacteria, known as oncobiotics (or their active substances), which are able to enhance the effect of cancer drugs.”
The researchers have planned to identify, in future studies, the specific parts of the bacteria responsible for enhancing the effects of cyclophosphamide. “If we succeed in answering this question, we can perhaps find a way of improving the survival of the patients treated using this chemotherapy by giving them drugs derived from these bacteria,” concludes Mathias Chamaillard.
[1] Unit 1019, “Center for Infection and Immunity of Lille” (Inserm/CNRS/University of Lille/Institut Pasteur Lille)
[2] Unit 1015, “Immunology of Tumours and Immunotherapy” (Inserm/Gustave Roussy Institute/Paris-Sud University)
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Enterococcus hirae and Barnesiella intestinihominis Facilitate Cyclophosphamide-Induced Therapeutic Immunomodulatory Effects Romain Daillère1,2,3, Marie Vétizou1,2,3, Nadine Waldschmitt4, Takahiro Yamazaki1,2, Christophe Isnard5,6, Vichnou Poirier-Colame1,2,3, Connie P. M. Duong1,2,7, Caroline Flament1,2,7, Patricia Lepage8, Maria Paula Roberti1,2,7, Bertrand Routy1,2,3, Nicolas Jacquelot1,2,3, Lionel Apetoh9,10,11, Sonia Becharef1,2,7, Sylvie Rusakiewicz1,2,7, Philippe Langella8, Harry Sokol8,12,13, Guido Kroemer14,15,16,17,18,19, David Enot1,15, Antoine Roux1,2,3,18, Alexander Eggermont1,3, Eric Tartour20,21, Ludger Johannes22,23,24, Paul-Louis Woerther25, Elisabeth Chachaty25, Jean-Charles Soria1,3, Benjamin Besse1,3, Encouse Golden26, Silvia Formenti26, Magdalena Plebanski27, Mutsa Madondo27, Philip Rosenstiel28, Didier Raoult29, Vincent Cattoir*5,6,30, Ivo Gomperts Boneca*31, Mathias Chamaillard*4 and Laurence Zitvogel1,2,3. 1 Institut de Cancérologie Gustave Roussy Cancer Campus (GRCC), 114 rue Edouard Vaillant, Villejuif, 94805, France ; 2 Institut National de la Santé Et de la Recherche Medicale (INSERM), U1015 and CICBT1428, GRCC, Villejuif, 94805, France 3 University of Paris-Saclay, Kremlin Bicêtre, 94270, France ; 4 University of Lille, CNRS, Inserm, CHRU Lille, Institut Pasteur de Lille, U1019-UMR 8204-CIIL, Centre d’Infection et d’Immunite´ de Lille, 59000 Lille, France; 5 Université de Caen Basse-Normandie, EA4655 U2RM (Équipe Antibio-Résistance), Caen, 14033, France ; 6 CHU de Caen, Service de Microbiologie, Caen, 14033, France ; 7 Center of Clinical Investigations in Biotherapies of Cancer (CICBT) 1428, Villejuif, 94805, France ; 8 Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, 78350 Jouy-en-Josas, France ; 9 Lipids, Nutrition, Cancer, INSERM, U866, Dijon, 21078, France ; 10 Department of Medicine, Université de Bourgogne Franche-Comté, Dijon, 21078, France ; 11 Department of Oncology, Centre Georges François Leclerc, Dijon, 21000, France ; 12 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 ; 13 Service de Gastroentérologie, Hôpital Saint-Antoine, Assistance Publique—Hôpitaux de Paris (APHP), Paris, 75012, France ; 14 INSERM U848, 94805 Villejuif, France ; 15 Metabolomics Platform, Institut Gustave Roussy, Villejuif, 94805, France ; 16 Equipe 11 labellisée Ligue contre le Cancer, Centre de Recherche des Cordeliers, INSERM U 1138, Paris, 75006, France ; 17 Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, 75015, France ; 18 Université Paris Descartes, Sorbonne Paris Cité, Paris, 75006, France ; 19 Karolinska Institute, Department of Women's and Children's Health, Karolinska University Hospital, Stockholm, 17176, Sweden ; 20 INSERM U970, Paris Cardiovascular Research Center, Université Paris-Descartes, Sorbonne Paris Cité, Paris, 75015, France ; 21 Service d’immunologie biologique, Hôpital Européen Georges Pompidou, Paris, 75015 France ; 22 INSERM U1143, 75005 Paris, France ; 23 Institut Curie, PSL Research University, Endocytic Trafficking and Therapeutic Delivery group, Paris, 75248, France ; 24 CNRS UMR 3666, Paris, 75005, France ; 25 Service de microbiologie, GRCC, Villejuif, 94805, France ; 26 Department of Radiation Oncology, Weill Cornell Medicine, New York, NY, USA ; 27 Department of Immunology and Pathology, Monash University, Alfred Hospital Precinct, Melbourne, Prahran, Victoria 3181, Australia ; 28 Institute of Clinical Molecular Biology, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany ; 29 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 ; 30 CNR de la Résistance aux Antibiotiques, Laboratoire Associé Entérocoques, Caen, 14033, France ; 31 Institut Pasteur, Unit Biology and Genetics of the bacterial Cell Wall, Paris, 75015, France ; *All three authors equally contributed to this work. Immunity http://dx.doi.org/10.1016/j.immuni.2016.09.009