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8 results on '"Iebba, V"'

1. Fecal Microbial Transplantation impact on gut microbiota composition and metabolome, microbial translocation and T-lymphocyte immune activation in recurrent Clostridium difficile infection patients

Author

Bruno, G., Gagliardi, A., Oliva, A., Trancassini, M., Macone, A., Cicerone, C., D’abramo, A., Iebba, V., Auria, S., Giulia Bonfiglio, Zingaropoli, M. A., D’ettorre, G., Badiali, D., Vullo, V., Corazziari, E. S., Schippa, S., Bruno, G., Gagliardi, A., Oliva, A., Trancassini, M., Macone, A., Cicerone, C., D'Abramo, A., Iebba, V., Auria, S., Bonfiglio, G., Zingaropoli, M. A., D'Ettorre, G., Badiali, D., Vullo, V., Corazziari, E. S., and Schippa, S.

Subjects
Aged, 80 and over, Male, microbial translocation, gut microbiota, recurrent clostridium difficile infection, Clostridioides difficile, T-Lymphocytes, fecal microbiota transplantation, Fecal Microbiota Transplantation, Middle Aged, Gastrointestinal Microbiome, Feces, Treatment Outcome, Recurrence, T-cell activation, Clostridium Infections, Metabolome, metabolome, Humans, Female, Aged
Abstract

This short communication reports the preliminary results of Fecal Microbial Transplantation (FMT) impact on microbiota, microbial translocation (MT), and immune activation in four recurrent Clostridium difficile infection (R-CDI) patients. After FMT a restore of gut microbiota composition with a significant increase of fecal acetyl-putrescine and spermidine and fecal acetate and butyrate, a decrease of immune activation of T cells CD4+ and CD8+levels, and of LPS binding protein (LBP) level, were observed. Preliminary results indicate that FMT seems to be helpful not only as a CDI radical cure, with an impact on fecal microbiota and metabolome profiles, but also on MT and immune activation.

2. Intestinal microbiota influences clinical outcome and side effects of early breast cancer treatment

Author

Andrew Maltez Thomas, Aude Sirven, Filippo Pietrantonio, Romy Aarnoutse, Carlos Caldas, Sibille Everhard, Marine Fidelle, Valerio Iebba, Fanny Aprahamian, Stergios Christodoulidis, Sylvère Durand, Lisa Derosa, Sibylle Loibl, Janine Ziemons, François Ghiringhelli, Carsten Denkert, Suzette Delaloge, Nicola Segata, Edoardo Pasolli, Anne-Laure Martin, Nitharsshini Nirmalathasan, Safae Terrisse, Laurence Zitvogel, Fabrice Andre, Marjolein L. Smidt, Guido Kroemer, Ines Vaz-Luis, Bertrand Routy, Claudia Iglesias, Terrisse, Safae, Derosa, Lisa, Iebba, Valerio, Ghiringhelli, Françoi, Vaz-Luis, Ine, Kroemer, Guido, Fidelle, Marine, Christodoulidis, Stergio, Segata, Nicola, Thomas, Andrew Maltez, Martin, Anne-Laure, Sirven, Aude, Everhard, Sibille, Aprahamian, Fanny, Nirmalathasan, Nitharsshini, Aarnoutse, Romy, Smidt, Marjolein, Ziemons, Janine, Caldas, Carlo, Loibl, Sibylle, Denkert, Carsten, Durand, Sylvere, Iglesias, Claudia, Pietrantonio, Filippo, Routy, Bertrand, André, Fabrice, Pasolli, Edoardo, Delaloge, Suzette, Zitvogel, Laurence, Institut Gustave Roussy (IGR), Faculté de médecine de l'Université Paris-Sud [Kremlin Bicêtre, Paris], Université Paris-Saclay, Immunologie des tumeurs et immunothérapie (UMR 1015), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre d'Investigation Clinique Biothérapie [Paris] (CICBT), Institut Curie [Paris], Immunologie anti-tumorale et immunothérapie des cancers (ITIC), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Institut de médecine génomique et d’immunothérapie (Genomic and Immunotherapy Medical Institute) (institut GIMI), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC)-FHU TRANSLAD (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Biomarqueurs prédictifs et nouvelles stratégies moléculaires en thérapeutique anticancéreuse (U981), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), University of Trento [Trento], Università degli studi di Trieste = University of Trieste, Centre for Integrative Biology (CIBIO), University of Trento (CIBIO), Maastricht University [Maastricht], University of Cambridge [UK] (CAM), Goethe-University Frankfurt am Main, Philipps Universität Marburg = Philipps University of Marburg, IRCCS Istituto Nazionale dei Tumori [Milano], Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM), Prédicteurs moléculaires et nouvelles cibles en oncologie (PMNCO), University of Naples Federico II = Università degli studi di Napoli Federico II, ANR-16-RHUS-0008,LUMIERE,LUMIERE(2016), European Project: 825410,ONCOBIOME, RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, Surgery, MUMC+: MA Heelkunde (9), UNICANCER-UNICANCER-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-FHU TRANSLAD (CHU de Dijon), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPC), University of Trieste, University of Naples Federico II, Ghiringhelli, François [0000-0002-5465-8305], Kroemer, Guido [0000-0002-9334-4405], Christodoulidis, Stergios [0000-0002-8773-1070], Segata, Nicola [0000-0002-1583-5794], Thomas, Andrew Maltez [0000-0001-5789-3354], Aarnoutse, Romy [0000-0002-8713-9747], Ziemons, Janine [0000-0002-4559-5488], Caldas, Carlos [0000-0003-3547-1489], Zitvogel, Laurence [0000-0003-1596-0998], Apollo - University of Cambridge Repository, Terrisse, S., Derosa, L., Iebba, V., Ghiringhelli, F., Vaz-Luis, I., Kroemer, G., Fidelle, M., Christodoulidis, S., Segata, N., Thomas, A. M., Martin, A. -L., Sirven, A., Everhard, S., Aprahamian, F., Nirmalathasan, N., Aarnoutse, R., Smidt, M., Ziemons, J., Caldas, C., Loibl, S., Denkert, C., Durand, S., Iglesias, C., Pietrantonio, F., Routy, B., Andre, F., Pasolli, E., Delaloge, S., and Zitvogel, L.

Subjects
Oncology, medicine.medical_treatment, [SDV]Life Sciences [q-bio], GUT MICROBIOME, THERAPY, Breast cancer, Breast Neoplasms, Female, Gastrointestinal Microbiome, Humans, Prognosis, Prospective Studies, Treatment Outcome, TUMOR-INFILTRATING LYMPHOCYTES, Prospective cohort study, Cancer, Early breast cancer, Microbiota, ADENOSINE, SOLID TUMORS, Intestinal Microbiome, Immunotherapy, PATHOLOGISTS, Adjuvant, Shotgun metagenomics, medicine.medical_specialty, CARCINOMA, CANTO study, Article, Immune system, STANDARDIZED METHOD, Internal medicine, medicine, Chemotherapy, Clinical significance, metagenomic, IMMUNOTHERAPY, Molecular Biology, metagenomics, business.industry, neoadjuvant, Cell Biology, Translational research, EFFICACY, networks, network, business
Abstract

The prognosis of early breast cancer (BC) relies on cell autonomous and immune parameters. The impact of the intestinal microbiome on clinical outcome has not yet been evaluated. Shotgun metagenomics was used to determine the composition of the fecal microbiota in 121 specimens from 76 early BC patients, 45 of whom were paired before and after chemotherapy. These patients were enrolled in the CANTO prospective study designed to record the side effects associated with the clinical management of BC. We analyzed associations between baseline or post-chemotherapy fecal microbiota and plasma metabolomics with BC prognosis, as well as with therapy-induced side effects. We examined the clinical relevance of these findings in immunocompetent mice colonized with BC patient microbiota that were subsequently challenged with histo-compatible mouse BC and chemotherapy. We conclude that specific gut commensals that are overabundant in BC patients compared with healthy individuals negatively impact BC prognosis, are modulated by chemotherapy, and may influence weight gain and neurological side effects of BC therapies. These findings obtained in adjuvant and neoadjuvant settings warrant prospective validation.

Published
2021
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3. Gut microbiota signatures are associated with toxicity to combined CTLA-4 and PD-1 blockade

Author

Catalin Mihalcioiu, Charlotte E. Ariyan, Michael K. Wong, Aurélie Fluckiger, Julie M. Simon, Rossanna C. Pezo, Michael G. White, Padmanee Sharma, Michael A. Postow, Sapna Pradyuman Patel, Adi Diab, Isabella C. Glitza, Elizabeth M. Burton, Whijae Roh, Zachary A. Cooper, Laurence Zitvogel, Maria Paula Roberti, Wen-Jen Hwu, Alexandria P. Cogdill, Miles C. Andrews, Gladys Ferrere, Abdul Wadud Khan, Scott E. Woodman, Robert R. Jenq, Christine N. Spencer, James P. Allison, Lisa Derosa, Curtis Gumbs, Wei Shen Chen, Stephanie S. Watowich, Irina Fernandez Curbelo, Michael A. Davies, Paule Opolon, Connie P.M. Duong, Jennifer A. Wargo, Maryam Tidjani Alou, Courtney W. Hudgens, Vancheswaran Gopalakrishnan, Pierre Olivier Gaudreau, Michael T. Tetzlaff, Didier Raoult, Arielle Elkrief, Khalida Wani, Jeffrey E. Gershenwald, Margaret K. Callahan, Sarah B. Johnson, Alexandre Reuben, Joseph F. Petrosino, Latasha Little, Peter A. Prieto, Matthew Lastrapes, Valerio Iebba, Bertrand Routy, Matthew Adamow, Alexander J. Lazar, Jennifer L. McQuade, Nadim J. Ajami, Golnaz Morad, Rodabe N. Amaria, Matthew C. Wong, Erez N. Baruch, Hussein Abdul-Hassan Tawbi, Satoru Yonekura, Li Zhao, Reetakshi Arora, Luis M Vence, Lauren E. Haydu, Luigi Nezi, Patrick Hwu, P. Andrew Futreal, Jianhua Zhang, The University of Texas M.D. Anderson Cancer Center [Houston], Olivia Newton-John Cancer Research Institute [Heidelberg, VIC, Australia], Monash University [Melbourne], Institut Gustave Roussy (IGR), Immunologie des tumeurs et immunothérapie (UMR 1015), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris-Saclay, Morsani College of Medicine [Tampa, USA], University of South Florida [Tampa] (USF), The Parker Institute, University of Copenhagen = Københavns Universitet (UCPH), AstraZeneca, Gaithersburg, MD, USA, University of Rochester Medical Center (URMC), Memorial Sloane Kettering Cancer Center [New York], Istituto Europeo di Oncologia, Milan, Microbes évolution phylogénie et infections (MEPHI), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Institut Hospitalier Universitaire Méditerranée Infection (IHU Marseille), McGill University Health Center [Montreal] (MUHC), University of Toronto, Baylor College of Medicine (BCM), Baylor University, ANR-16-RHUS-0008,LUMIERE,LUMIERE(2016), ANR-10-IAHU-0003,Méditerranée Infection,I.H.U. Méditerranée Infection(2010), European Project: 825410,ONCOBIOME, COMBE, Isabelle, LUMIERE - - LUMIERE2016 - ANR-16-RHUS-0008 - RHUS - VALID, Instituts Hospitalo-Universitaires - I.H.U. Méditerranée Infection - - Méditerranée Infection2010 - ANR-10-IAHU-0003 - IAHU - VALID, European Union’s Horizon 2020 research and innovation programme under grant agreement. - ONCOBIOME - 825410 - INCOMING, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Department of Radiology, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, France, University of Copenhagen = Københavns Universitet (KU), Immunologie anti-tumorale et immunothérapie des cancers (ITIC), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM), Institut de Recherche pour le Développement (IRD)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPC), Institut Universitaire de France (IUF), Ministère de l'Education nationale, de l’Enseignement supérieur et de la Recherche (M.E.N.E.S.R.), Faculté de médecine de l'Université Paris-Sud [Kremlin Bicêtre, Paris], Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Malaria : parasites et hôtes - Malaria : parasites and hosts, Institut Pasteur [Paris], Ottawa Hospital Research Institute [Ottawa] (OHRI), Andrews, M. C., Duong, C. P. M., Gopalakrishnan, V., Iebba, V., Chen, W. -S., Derosa, L., Khan, M. A. W., Cogdill, A. P., White, M. G., Wong, M. C., Ferrere, G., Fluckiger, A., Roberti, M. P., Opolon, P., Alou, M. T., Yonekura, S., Roh, W., Spencer, C. N., Curbelo, I. F., Vence, L., Reuben, A., Johnson, S., Arora, R., Morad, G., Lastrapes, M., Baruch, E. N., Little, L., Gumbs, C., Cooper, Z. A., Prieto, P. A., Wani, K., Lazar, A. J., Tetzlaff, M. T., Hudgens, C. W., Callahan, M. K., Adamow, M., Postow, M. A., Ariyan, C. E., Gaudreau, P. -O., Nezi, L., Raoult, D., Mihalcioiu, C., Elkrief, A., Pezo, R. C., Haydu, L. E., Simon, J. M., Tawbi, H. A., Mcquade, J., Hwu, P., Hwu, W. -J., Amaria, R. N., Burton, E. M., Woodman, S. E., Watowich, S., Diab, A., Patel, S. P., Glitza, I. C., Wong, M. K., Zhao, L., Zhang, J., Ajami, N. J., Petrosino, J., Jenq, R. R., Davies, M. A., Gershenwald, J. E., Futreal, P. A., Sharma, P., Allison, J. P., Routy, B., Zitvogel, L., and Wargo, J. A.

Subjects
[SDV]Life Sciences [q-bio], medicine.medical_treatment, Interleukin-1beta, Programmed Cell Death 1 Receptor, Cancer immunotherapy, Gut flora, Inbred C57BL, Mice, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Medicine, CTLA-4 Antigen, Melanoma, ComputingMilieux_MISCELLANEOUS, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.MHEP.ME] Life Sciences [q-bio]/Human health and pathology/Emerging diseases, 0303 health sciences, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, Tumor, biology, General Medicine, 3. Good health, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, 030220 oncology & carcinogenesis, Toxicity, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Female, [SDV.MP.PAR] Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Human, General Biochemistry, Genetics and Molecular Biology, Cell Line, 03 medical and health sciences, Immune system, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Cell Line, Tumor, Animals, Humans, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Microbiome, Colitis, 030304 developmental biology, Animal, business.industry, medicine.disease, biology.organism_classification, Mice, Inbred C57BL, Gastrointestinal Microbiome, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Immune checkpoint, CTLA-4, Immunology, [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, business
Abstract

International audience; Treatment with combined immune checkpoint blockade (CICB) targeting CTLA-4 and PD-1 is associated with clinical benefit across tumor types, but also a high rate of immune-related adverse events. Insights into biomarkers and mechanisms of response and toxicity to CICB are needed. To address this, we profiled the blood, tumor and gut microbiome of 77 patients with advanced melanoma treated with CICB, with a high rate of any ≥grade 3 immune-related adverse events (49%) with parallel studies in pre-clinical models. Tumor-associated immune and genomic biomarkers of response to CICB were similar to those identified for ICB monotherapy, and toxicity from CICB was associated with a more diverse peripheral T-cell repertoire. Profiling of gut microbiota demonstrated a significantly higher abundance of Bacteroides intestinalis in patients with toxicity, with upregulation of mucosal IL-1β in patient samples of colitis and in pre-clinical models. Together, these data offer potential new therapeutic angles for targeting toxicity to CICB.

Published
2021
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4. Ketogenic diet and ketone bodies enhance the anticancer effects of PD-1 blockade

Author

Carolina Alves Costa Silva, Deborah Lefevre, Lisa Derosa, Claudia Grajeda-Iglesias, Gladys Ferrere, Maryam Tidjani Alou, Anne-Gaëlle Goubet, Fanny Aprahamian, Conrad Rauber, Didier Raoult, Aurélie Fluckiger, Monica Arnedos, Damien Drubay, Romain Daillère, Cassandra Thelemaque, Tim D. Spector, Sylvère Durand, Liwei Zhao, Guido Kroemer, Emeline Colomba, Oliver Kepp, Valerio Iebba, Laurence Zitvogel, Nicola Segata, Francesco Asnicar, Marine Fidelle, Peng Liu, Bernhard Ryffel, Immunologie intégrative des tumeurs et immunothérapie des cancers (INTIM), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Università degli studi di Trieste = University of Trieste, Immunologie et Neurogénétique Expérimentales et Moléculaires (INEM), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS), Institut Gustave Roussy (IGR), Oncologie gynécologique, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Pathologie mammaire, Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Microbes évolution phylogénie et infections (MEPHI), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Institut Hospitalier Universitaire Méditerranée Infection (IHU Marseille), Centre for Integrative Biology (CIBIO), University of Trento (CIBIO), University of Trento [Trento], King‘s College London, Centre d'Investigation Clinique en Biotherapie des cancers (CIC 1428 , CBT 507 ), Institut Gustave Roussy (IGR)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), ANR-16-RHUS-0008,LUMIERE,LUMIERE(2016), European Project: 825410,ONCOBIOME, Ferrere, G., Alou, M. T., Liu, P., Goubet, A. -G., Fidelle, M., Kepp, O., Durand, S., Iebba, V., Fluckiger, A., Daillere, R., Thelemaque, C., Grajeda-Iglesias, C., Silva, C. A. C., Aprahamian, F., Lefevre, D., Zhao, L., Ryffel, B., Colomba, E., Arnedos, M., Drubay, D., Rauber, C., Raoult, D., Asnicar, F., Spector, T., Segata, N., Derosa, L., Kroemer, G., Zitvogel, L., Gestionnaire, Hal Sorbonne Université, LUMIERE - - LUMIERE2016 - ANR-16-RHUS-0008 - RHUS - VALID, European Union’s Horizon 2020 research and innovation programme under grant agreement. - ONCOBIOME - 825410 - INCOMING, École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), University of Trieste, Centre National de la Recherche Scientifique (CNRS)-Université d'Orléans (UO), and Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, Ketogenic, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Programmed Cell Death 1 Receptor, Cancer, Immunotherapy, Metabolism, Mouse models, Oncology, 3-Hydroxybutyric Acid, Animals, CTLA-4 Antigen, Cell Line, Tumor, Combined Modality Therapy, Female, Gastrointestinal Microbiome, Humans, Immune Checkpoint Inhibitors, Ketone Bodies, Kidney Neoplasms, Melanoma, Experimental, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Neoplasms, Experimental, Receptors, G-Protein-Coupled, Diet, Ketogenic, Pharmacology, CXCR3, Inbred C57BL, 0302 clinical medicine, Neoplasms, Ketogenesis, Receptors, Ketone Bodie, Melanoma, Inbred BALB C, Tumor, Chemistry, Kidney Neoplasm, General Medicine, 3. Good health, [SDV] Life Sciences [q-bio], Immunosurveillance, 030220 oncology & carcinogenesis, Ketone bodies, Medicine, Human, Research Article, Immune Checkpoint Inhibitor, Mouse model, Cell Line, 03 medical and health sciences, Experimental, G-Protein-Coupled, Downregulation and upregulation, medicine, Animal, Immune checkpoint, Diet, 030104 developmental biology, Ketogenic diet
Abstract

International audience; Limited experimental evidence bridges nutrition and cancer immunosurveillance. Here, we show that ketogenic diet (KD) - or its principal ketone body, 3-hydroxybutyrate (3HB), most specifically in intermittent scheduling - induced T cell-dependent tumor growth retardation of aggressive tumor models. In conditions in which anti-PD-1 alone or in combination with anti-CTLA-4 failed to reduce tumor growth in mice receiving a standard diet, KD, or oral supplementation of 3HB reestablished therapeutic responses. Supplementation of KD with sucrose (which breaks ketogenesis, abolishing 3HB production) or with a pharmacological antagonist of the 3HB receptor GPR109A abolished the antitumor effects. Mechanistically, 3HB prevented the immune checkpoint blockade-linked upregulation of PD-L1 on myeloid cells, while favoring the expansion of CXCR3+ T cells. KD induced compositional changes of the gut microbiota, with distinct species such as Eisenbergiella massiliensis commonly emerging in mice and humans subjected to carbohydrate-low diet interventions and highly correlating with serum concentrations of 3HB. Altogether, these results demonstrate that KD induces a 3HB-mediated antineoplastic effect that relies on T cell-mediated cancer immunosurveillance.

Published
2021
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5. Cross-reactivity between tumor MHC class I-restricted antigens and an enterococcal bacteriophage

Author

Fathia Mami-Chouaib, Vincent Cattoir, Guido Kroemer, Mohamed Sassi, Krisztián Papp, Nathalie Labarrière, Valerio Iebba, Valentin Quiniou, Romain Boidot, Zsofia Sztupinszki, Nicola Segata, Ivo G. Boneca, Friedemann Loos, Sylvain Simon, Jacques Bou-Khalil, Richard J. Wheeler, Carlos López-Otín, Andréanne Gagné, Luisa De Sordi, Barbara S. Sixt, Philippe Joubert, Clara-Maria Scarlata, Fabien Lemaitre, Peng Liu, Laurent Debarbieux, Alexander M.M. Eggermont, Paola Nisticò, Didier Raoult, David Klatzmann, Connie P.M. Duong, Belinda Palermo, Lisa Derosa, Maha Ayyoub, Maryam Tidjani Alou, Meriem Messaoudene, B. Escudier, François Ghiringhelli, Aurélie Fluckiger, Gladys Ferrere, Saber Khelaifia, Bertrand Routy, Laurence Albiges, Edoardo Pasolli, Anne Gaëlle Goubet, Zoltan Szallasi, Romain Daillère, István Csabai, Laurence Zitvogel, Fabrice Andre, Francesco Facciolo, Corentin Richard, Catherine Rabu, Institut Gustave Roussy (IGR), Immunologie anti-tumorale et immunothérapie des cancers (ITIC), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, ARN régulateurs bactériens et médecine (BRM), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Umeå University, Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Centre d'oncologie et de radiothérapie du parc [Dijon], Institut de médecine génomique et d’immunothérapie (Genomic and Immunotherapy Medical Institute) (institut GIMI), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC)-FHU TRANSLAD (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Anti-Tumor Immunosurveillance and Immunotherapy (CRCINA-ÉQUIPE 3), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Microbes évolution phylogénie et infections (MEPHI), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Université Paris-Saclay, Institut Universitaire de Cardiologie et de Pneumologie de Québec (IUCPQ), Université Laval [Québec] (ULaval), Institut Pasteur [Paris] (IP), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), National Cancer Institute Regina Elena [Rome, Italy], Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Boston Children's Hospital, Harvard Medical School [Boston] (HMS), Eötvös Loránd University (ELTE), University of Trento [Trento], Universidad de Oviedo [Oviedo], Centre d'investigation clinique Biothérapie [CHU Pitié-Salpêtrière] (CIC-BTi), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Immunologie intégrative des tumeurs et immunothérapie des cancers (INTIM), Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM), Centre National de Référence de la Résistance aux Antibiotiques [CHU Rennes] (CNR), CHU Pontchaillou [Rennes], Institut Universitaire de France (IUF), Ministère de l'Education nationale, de l’Enseignement supérieur et de la Recherche (M.E.N.E.S.R.), ANR-16-RHUS-0008,LUMIERE,LUMIERE(2016), ANR-19-CE15-0029,Ileobiome,Régulation des réponses immunitaires iléales dans l'immunosurveillance du cancer du colon: rôle du microbiote et des antigènes des cellules souches.(2019), Bernardo, Elizabeth, École pratique des hautes études (EPHE), UNICANCER-UNICANCER-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-FHU TRANSLAD (CHU de Dijon), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre d'investigation clinique pluridisciplinaire [CHU Pitié Salpêtrière] (CIC-P 1421), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Genetic and Immunology Medical Institute (GIMI), UNICANCER-UNICANCER-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté]), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Institut Pasteur [Paris], Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Centre d’Investigation Clinique intégré en Biothérapies et immunologie [AP-HP pitié-salpêtrière, Paris] (CIC-BTi), CHU Pitié-Salpêtrière [AP-HP], Fluckiger, A., Daillere, R., Sassi, M., Sixt, B. S., Liu, P., Loos, F., Richard, C., Rabu, C., Alou, M. T., Goubet, A. -G., Lemaitre, F., Ferrere, G., Derosa, L., Duong, C. P. M., Messaoudene, M., Gagne, A., Joubert, P., De Sordi, L., Debarbieux, L., Simon, S., Scarlata, C. -M., Ayyoub, M., Palermo, B., Facciolo, F., Boidot, R., Wheeler, R., Boneca, I. G., Sztupinszki, Z., Papp, K., Csabai, I., Pasolli, E., Segata, N., Lopez-Otin, C., Szallasi, Z., Andre, F., Iebba, V., Quiniou, V., Klatzmann, D., Boukhalil, J., Khelaifia, S., Raoult, D., Albiges, L., Escudier, B., Eggermont, A., Mami-Chouaib, F., Nistico, P., Ghiringhelli, F., Routy, B., Labarriere, N., Cattoir, V., Kroemer, G., Zitvogel, L., and de Sordi, L.

Subjects
H-2 Antigen, Programmed Cell Death 1 Receptor, CD8-Positive T-Lymphocytes, Epitope, Epitopes, Feces, Mice, 0302 clinical medicine, Enterococcus hirae, Neoplasms, Monoclonal, Bacteriophages, 0303 health sciences, Multidisciplinary, biology, Antibodies, Monoclonal, Viral Tail Proteins, Alkylating, 3. Good health, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Cross Reaction, Immunotherapy, Human, T cell, Antineoplastic Agents, [SDV.CAN]Life Sciences [q-bio]/Cancer, Cross Reactions, Major histocompatibility complex, Antibodies, Microbiology, 03 medical and health sciences, Animals, Antigens, Neoplasm, Antineoplastic Agents, Alkylating, Cyclophosphamide, Gastrointestinal Microbiome, H-2 Antigens, Histocompatibility Antigens Class I, Humans, [SDV.CAN] Life Sciences [q-bio]/Cancer, Antigen, MHC class I, medicine, Antigens, Bacteriophage, Prophage, 030304 developmental biology, Animal, CD8-Positive T-Lymphocyte, biology.organism_classification, biology.protein, Neoplasm, Fece, CD8
Abstract

International audience; Intestinal microbiota have been proposed to induce commensal-specific memory T cells that cross-react with tumor-associated antigens. We identified major histocompatibility complex (MHC) class I-binding epitopes in the tail length tape measure protein (TMP) of a prophage found in the genome of the bacteriophage Enterococcus hirae Mice bearing E. hirae harboring this prophage mounted a TMP-specific H-2Kb-restricted CD8+ T lymphocyte response upon immunotherapy with cyclophosphamide or anti-PD-1 antibodies. Administration of bacterial strains engineered to express the TMP epitope improved immunotherapy in mice. In renal and lung cancer patients, the presence of the enterococcal prophage in stools and expression of a TMP-cross-reactive antigen by tumors correlated with long-term benefit of PD-1 blockade therapy. In melanoma patients, T cell clones recognizing naturally processed cancer antigens that are cross-reactive with microbial peptides were detected.

Published
2020
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6. Gut Bacteria Composition Drives Primary Resistance to Cancer Immunotherapy in Renal Cell Carcinoma Patients

Author

Conrad Rauber, Gladys Ferrere, Jean-Eudes Fahrner, Valerio Iebba, Nicolas Pons, Romain Daillère, Emmanuelle Le Chatellier, Hugo Roume, Filippo Pietrantonio, Nicola Segata, Marine Fidelle, Anne-Gaëlle Goubet, Carolina Alves Costa Silva, Bertrand Routy, Connie P.M. Duong, Karim Fizazi, Edoardo Pasolli, Safae Terrisse, Beatrice Casu, Laurence Albiges, Bernard Escudier, Mélodie Bonvalet, Maryam Tidjani Alou, Laurie Alla, Kristina Iribarren, Didier Raoult, Aude Desnoyer, Guido Kroemer, Lisa Derosa, Laura Mondragón, Nathalie Galleron, Anna Reni, Fabien Lemaitre, Laurence Zitvogel, Derosa, L., Routy, B., Fidelle, M., Iebba, V., Alla, L., Pasolli, E., Segata, N., Desnoyer, A., Pietrantonio, F., Ferrere, G., Fahrner, J. -E., Le Chatellier, E., Pons, N., Galleron, N., Roume, H., Duong, C. P. M., Mondragon, L., Iribarren, K., Bonvalet, M., Terrisse, S., Rauber, C., Goubet, A. -G., Daillere, R., Lemaitre, F., Reni, A., Casu, B., Alou, M. T., Alves Costa Silva, C., Raoult, D., Fizazi, K., Escudier, B., Kroemer, G., Albiges, L., Zitvogel, L., Immunologie anti-tumorale et immunothérapie des cancers (ITIC), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Faculté de médecine de l'Université Paris-Sud [Kremlin Bicêtre, Paris], Université Paris-Saclay, Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM), MetaGenoPolis (MGP (US 1367)), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), University of Naples Federico II = Università degli studi di Napoli Federico II, Centre for Integrative Biology (CIBIO), University of Trento (CIBIO), University of Trento [Trento], Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse (AMMICa), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Gustave Roussy (IGR), IRCCS Istituto Nazionale dei Tumori [Milano], Université Paris-Sud - Paris 11 (UP11), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Microbes évolution phylogénie et infections (MEPHI), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Institut Hospitalier Universitaire Méditerranée Infection (IHU Marseille), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Suzhou Institute of Systems Medicine [Jiangsu, P.R. China], Karolinska University Hospital [Stockholm], Philanthropia Foundation ESMO translational research fellowship Fonds de la Recherche en Sante du Quebec Kidney Cancer Research Network of Canada Ligue nationale contre le cancerFrench National Research Agency (ANR)French National Research Agency (ANR)ERA-Net for Research on Rare Diseases Fondation ARC pour la Recherche sur le CancerRegion Ile-de-France Fondation de FranceFondation pour la Recherche MedicaleEuropean Commission Joint Research CentreEuropean Research Council (ERC)Fondation Carrefour, High-end Foreign Expert Program in China GDW20171100085 GDW20181100051Institut National du Cancer (INCA) FranceInserm (HTE) Institut Universitaire de France Leducq FoundationSearave and Carrefour Foundation SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE 2.0) BMS Foundation SIRIC Cancer Research and Personalized Medicine (CARPEM) Paris Alliance of Cancer Research Institutes (PACRI) Mediterranee Infection 10-IAHU-03Region Provence-Alpes-Cote d'AzurNational Research, Development and Innovation Fund of Hungary FIEK_16-1-20160005Research and Technology Innovation Fund NAP2-2017-1.2.1-NKP-0002Breast Cancer Research Foundation BCRF-17-156Novo Nordisk Foundation Interdisciplinary Synergy Program Grant NNF15OC0016584, ANR-16-RHUS-0008,LUMIERE,LUMIERE(2016), European Project: 825410,ONCOBIOME, University of Naples Federico II, Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Gustave Roussy Cancer Campus (GRCC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Saclay, Université Paris-Sud [Le Kremlin-Bicêtre] (Faculté de Médecine), Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Université de Montréal (UdeM)-Université de Montréal (UdeM), Centre d’Investigation Clinique en Biothérapies [CHU Pitié-Salpêtrière] (CIC-BT), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université, Université Paris-Saclay, Faculté de Pharmacie, 92290 Châtenay-Malabry, France, MetaGenoPolis, European Institute of Oncology [Milan] (ESMO), Gustave Roussy Cancer Campus, Partenaires INRAE, Chinese Academy of Medical Sciences, Philanthropia Foundation ESMO translational research fellowship.Fonds de la Recherche en Sante du Quebec Kidney Cancer Research Network of CanadaLigue nationale contre le cancerFrench National Research Agency (ANR) ERA-Net for Research on Rare DiseasesFondation ARC pour la Recherche sur le CancerRegion Ile-de-FranceFondation de FranceFondation pour la Recherche MedicaleEuropean Commission Joint ResearchCentre European Research Council (ERC)Fondation Carrefour, and High-end Foreign Expert Program in China GDW20171100085 GDW20181100051Institut National du Cancer (INCA) France Inserm (HTE) Institut Universitaire de FranceLeducq FoundationSearave and Carrefour Foundation SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE 2.0) BMS Foundation SIRIC Cancer Research and Personalized Medicine (CARPEM) Paris Alliance of Cancer Research Institutes (PACRI)Mediterranee Infection 10-IAHU-03Region Provence-Alpes-Cote d'AzurNational Research, Development and Innovation Fund of Hungary FIEK_16-1-20160005Research and Technology Innovation Fund NAP2-2017-1.2.1-NKP-0002Breast Cancer Research Foundation BCRF-17-156Novo Nordisk Foundation Interdisciplinary Synergy Program Grant NNF15OC0016584

Subjects
Oncology, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Antibiotics, 030232 urology & nephrology, Tyrosine kinase inhibitor, Immune checkpoint inhibitor, Tyrosine-kinase inhibitor, Feces, Mice, 0302 clinical medicine, Cancer immunotherapy, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Renal cell carcinoma, Prospective Studies, Immune Checkpoint Inhibitors, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, Microbiota, Kidney cancer, Kidney Neoplasms, 3. Good health, Nivolumab, 030220 oncology & carcinogenesis, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, medicine.medical_specialty, medicine.drug_class, Urology, [SDV.CAN]Life Sciences [q-bio]/Cancer, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Predictive Value of Tests, Internal medicine, medicine, Animals, Humans, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Carcinoma, Renal Cell, [SDV.EE.SANT]Life Sciences [q-bio]/Ecology, environment/Health, business.industry, Antibiotic, Immunotherapy, medicine.disease, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Immune checkpoint, Gastrointestinal Microbiome, Drug Resistance, Neoplasm, business
Abstract

Background: The development of immune checkpoint blockade (ICB) has revolutionized the clinical outcome of renal cell carcinoma (RCC). Nevertheless, improvement of durability and prediction of responses remain unmet medical needs. While it has been recognized that antibiotics (ATBs) decrease the clinical activity of ICB across various malignancies, little is known about the direct impact of distinct intestinal nonpathogenic bacteria (commensals) on therapeutic outcomes of ICB in RCC. Objective: To evaluate the predictive value of stool bacteria composition for ICB efficacy in a cohort of advanced RCC patients. Design, setting, and participants: We prospectively collected fecal samples from 69 advanced RCC patients treated with nivolumab and enrolled in the GETUG-AFU 26 NIVOREN microbiota translational substudy phase 2 trial (NCT03013335) at Gustave Roussy. We recorded patient characteristics including ATB use, prior systemic therapies, and response criteria. We analyzed 2994 samples of feces from healthy volunteers (HVs). In parallel, preclinical studies performed in RCC-bearing mice that received fecal transplant (FMT) from RCC patients resistant to ICB (NR-FMT) allowed us to draw a cause-effect relationship between gut bacteria composition and clinical outcomes for ICB. The influence of tyrosine kinase inhibitors (TKIs) taken before starting nivolumab on the microbiota composition has also been assessed. Outcome measurements and statistical analysis: Metagenomic data (MG) from whole genome sequencing (WGS) were analyzed by multivariate and pairwise comparisons/fold ratio to identify bacterial fingerprints related to ATB or prior TKI exposure and patients’ therapeutic response (overall response and progression-free survival), and compared with the data from cancer-free donors. Results and limitations: Recent ATB use (n = 11; 16%) reduced objective response rates (from 28% to 9%, p < 0.03) and markedly affected the composition of the microbiota, facilitating the dominance of distinct species such as Clostridium hathewayi, which were also preferentially over-represented in stools from RCC patients compared with HVs. Importantly, TKIs taken prior to nivolumab had implications in shifting the microbiota composition. To establish a cause-effect relationship between gut bacteria composition and ICB efficacy, NR-FMT mice were successfully compensated with either FMT from responding RCC patients or beneficial commensals identified by WGS-MG (Akkermansia muciniphila and Bacteroides salyersiae). Conclusions: The composition of the microbiota is influenced by TKIs and ATBs, and impacts the success of immunotherapy. Future studies will help sharpen the role of these specific bacteria and their potential as new biomarkers. Patient summary: We used quantitative shotgun DNA sequencing of fecal microbes as well as preclinical models of fecal or bacterial transfer to study the association between stool composition and (pre)clinical outcome to immune checkpoint blockade. Novel insights into the pathophysiological relevance of intestinal dysbiosis in the prognosis of kidney cancer may lead to innovative therapeutic solutions, such as supplementation with probiotics to prevent primary resistance to therapy. Antibiotics prior to immune checkpoint inhibitors have a deleterious clinical impact, reduce the microbiome diversity, and increase Clostridium hathewayi bacteria associated with resistance. Higher baseline microbiome diversity and Akkermansia muciniphila are associated with longer progression-free survival. In murine fecal microbiome transplantation experiments, A. muciniphila can restore the anticancer activity of the combination of anti–PD-1 and CTLA-4.

Published
2020
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7. High abundance of genus Prevotella is associated with dysregulation of IFN-I and T cell response in HIV-1-infected patients

Author

Guido Antonelli, Letizia Santinelli, Claudio Maria Mastroianni, Claudia Pinacchio, Giuseppe Pietro Innocenti, Valerio Iebba, Giancarlo Ceccarelli, Federica Frasca, Camilla Bitossi, Gabriella d'Ettorre, Giuseppe Oliveto, Mirko Scordio, Carolina Scagnolari, Pinacchio, C., Scagnolari, C., Iebba, V., Santinelli, L., Innocenti, G. P., Frasca, F., Bitossi, C., Scordio, M., Oliveto, G., Ceccarelli, G., Antonelli, G., Mastroianni, C. M., and D'Ettorre, G.

Subjects
Myxovirus Resistance Proteins, CD4-Positive T-Lymphocytes, 0301 basic medicine, Male, Prevotella, Pilot Projects, HIV Infections, Receptor, Interferon alpha-beta, CD8-Positive T-Lymphocytes, CD38, Lymphocyte Activation, Myxovirus Resistance Protein, Interferon alpha-beta, 0302 clinical medicine, Immunology and Allergy, Cytotoxic T cell, hiv, gut, microbiota, ifnβ, HIV Infection, 030212 general & internal medicine, biology, Middle Aged, Infectious Diseases, medicine.anatomical_structure, CD4-Positive T-Lymphocyte, Case-Control Studie, Receptor, Human, Adult, Immunology, Human leukocyte antigen, 03 medical and health sciences, medicine, Humans, Pilot Project, Alistipes, Lamina propria, HLA-DR Antigens, CD8-Positive T-Lymphocyte, Interferon-beta, biology.organism_classification, medicine.disease, ADP-ribosyl Cyclase 1, HLA-DR Antigen, Dysbiosi, 030104 developmental biology, Case-Control Studies, HIV-1, Dysbiosis, Bacteroides
Abstract

OBJECTIVE: HIV-1-associated dysbiosis is most commonly characterized by overall decreased diversity, with abundance of the genus Prevotella, recently related to inflammatory responses. DESIGN: A pilot study including 10 antiretroviral therapy-treated HIV-1-infected men and 50 uninfected controls was performed to identify the main gut dysbiosis determinants (e.g. Prevotella enrichment), that may affect mucosal antiviral defenses and T cell immunity in HIV-1-infected individuals. METHODS: 16rRNA gene sequencing was applied to the HIV-1-infected individuals' fecal microbiota and compared with controls. Measurements of CD4 and CD8 T cell activation [CD38, human leukocyte antigen (HLA)-DR, CD38 HLA-DR] and frequencies of Th17, obtained from lamina propria lymphocytes isolated from five different intestinal sites, were performed by flow cytometry. IFNβ, IFNAR1 and MxA gene expression level was evaluated by real-time PCR in lamina propria lymphocytes. Nonparametric t tests were used for statistical analysis. RESULTS: HIV-1-infected men had a significant fecal microbial communities' imbalance, including different levels of genera Faecalibacterium, Prevotella, Alistipes and Bacteroides, compared with controls. Notably, Prevotella abundance positively correlated with frequencies of CD4 T cells expressing CD38 or HLA-DR and coexpressing CD38 and HLA-DR (P

Published
2020

8. Dominant genotypes in mucosa-associated Escherichia coli strains from pediatric patients with inflammatory bowel disease

Author

Osvaldo Borrelli, Fernanda Chiarini, Salvatore Cucchiara, Marta Aleandri, Lucilla Seganti, Valerio Iebba, John Osborn, Catia Longhi, Serena Schippa, Maria Pia Conte, Schippa, S., Conte, M. P., Borrelli, O., Iebba, V., Aleandri, M., Seganti, L., Longhi, C., Chiarini, F., Osborn, J., and Cucchiara, S.

Subjects
DNA, Bacterial, Male, Adolescent, Genotype, IBD, Pediatric patients, Dominant genotypes, Virulence, Biology, medicine.disease_cause, Inflammatory bowel disease, Bacterial Adhesion, Dominant genotype, Mucosa-associated, Microbiology, Pathogenesis, Intestinal mucosa, Crohn Disease, Ileum, medicine, Escherichia coli, Immunology and Allergy, Humans, Intestinal Mucosa, Child, Escherichia coli Infections, Crohn's disease, Gastroenterology, E. coli, medicine.disease, Prognosis, Ulcerative colitis, Bacterial Typing Techniques, Immunology, Colitis, Ulcerative, Female, Caco-2 Cells
Abstract

Background: Studies performed in adults with inflammatory bowel disease (IBD) have suggested that mucosa-associated Escherichia coli strains may be involved in its pathogenesis. The aim of this study was to characterize E. coli strains from the intestinal mucosa of pediatric IBD patients to investigate whether a particular subset of strains could be associated with the disease. Methods: We analyzed the genomic and phenotypic traits of 60 E. coli strains isolated from biopsies of pediatric patients with Crohn's disease (CD), ulcerative colitis (UC), and from age-matched controls. Results: No noteworthy differences were found in the distribution of phylogroups. The percentage of adhesive E. coli strains was similar in biopsies from patients and controls. However, the adhesion ability of E. coli strains differed between ileal and colonic or rectal areas, only in the strains from CD and UC patients. The percentage of E. coli possessing more than 1 of the adhesive/virulence determinants was significantly higher in strains from UC than from CD and controls. Interestingly, the genetic profile examination revealed 2 large clusters of genetically linked E. coli strains from IBD patients. Ninety-two percent of the strains isolated from CD patients were in the first cluster (A) and were distributed between 2 genetic subclusters (A1 and A2), while a second cluster (B) contained most of the strains isolated from UC (78%; subcluster B1), and control strains (77%; subcluster B2). Conclusions: Genomic analysis of mucosa-associated E. coli strains found a close genetic association between strains isolated from CD and UC patients. (Inflamm Bowel Dis 2008)

Published
2009

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