Fluckiger et al. showed that an H-2Kb-restricted epitope in the TMP protein of phage that infect enterococci was homologous to amino acid sequences in the murine oncogenic driver proteasome subunit beta type-4 (PSMB4) and in the human glycerol-3-phosphate dehydrogenase1-like (GPD1-L) protein, which restrains oncogenic HIF1A. Treatment of tumor-bearing mice with TMP induced TMP-specific/PSMB4 peptide cross-reactive CD8+ T cell recall responses and reduced growth of PSMB4-overexpressing tumors. Anti-PD-1 had more benefit in patients with a TMP sequence in their fecal enterococci or with tumors expressing TMP-like GPD1-L epitopes.
Contributed by Paula Hochman
ABSTRACT: 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-2K(b)-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.
Author Info: (1) Gustave Roussy Cancer Campus (GRCC), Villejuif, France. Institut National de la Sant et de la Recherche Mdicale, U1015, Institut Gustave Roussy, Villejuif, France. (2) Gustave
Author Info: (1) Gustave Roussy Cancer Campus (GRCC), Villejuif, France. Institut National de la Sant et de la Recherche Mdicale, U1015, Institut Gustave Roussy, Villejuif, France. (2) Gustave Roussy Cancer Campus (GRCC), Villejuif, France. Institut National de la Sant et de la Recherche Mdicale, U1015, Institut Gustave Roussy, Villejuif, France. everImmune, Gustave Roussy Cancer Center, Villejuif, France. (3) Universit Rennes 1, Laboratoire de Biochimie Pharmaceutique, Inserm U1230 - UPRES EA 2311, Rennes, France. (4) Laboratory for Molecular Infection Medicine Sweden, Ume Centre for Microbial Research, Department of Molecular Biology, Ume University, 90187, Ume, Sweden. Cell Biology and Metabolomics Platforms, Gustave Roussy Cancer Campus, Villejuif, France. Equipe 11 labellise Ligue contre le Cancer, Centre de Recherche des Cordeliers, Paris, France. INSERM U1138, Paris, France. Universit de Paris, Paris, France. Sorbonne Universit, Paris, France. (5) Cell Biology and Metabolomics Platforms, Gustave Roussy Cancer Campus, Villejuif, France. Equipe 11 labellise Ligue contre le Cancer, Centre de Recherche des Cordeliers, Paris, France. INSERM U1138, Paris, France. Universit de Paris, Paris, France. Sorbonne Universit, Paris, France. (6) Cell Biology and Metabolomics Platforms, Gustave Roussy Cancer Campus, Villejuif, France. Equipe 11 labellise Ligue contre le Cancer, Centre de Recherche des Cordeliers, Paris, France. INSERM U1138, Paris, France. Universit de Paris, Paris, France. Sorbonne Universit, Paris, France. (7) Research Platform in Biological Oncology, Dijon, France. GIMI Genetic and Immunology Medical Institute, Dijon, France. University of Burgundy-Franche Comt, Dijon, France. (8) CRCINA, INSERM, Universit d'Angers, Universit de Nantes, Nantes, France. LabEx IGO "Immunotherapy, Graft, Oncology," Nantes, France. (9) Gustave Roussy Cancer Campus (GRCC), Villejuif, France. Institut National de la Sant et de la Recherche Mdicale, U1015, Institut Gustave Roussy, Villejuif, France. UMR MEPHI, Aix-Marseille Universit, IRD, AP-HM, Institut Hospitalo-Universitaire Mditerrane-Infection, 19-21 Boulevard Jean Moulin, 13385, Marseille cedex 05, France. (10) Gustave Roussy Cancer Campus (GRCC), Villejuif, France. Institut National de la Sant et de la Recherche Mdicale, U1015, Institut Gustave Roussy, Villejuif, France. (11) Gustave Roussy Cancer Campus (GRCC), Villejuif, France. everImmune, Gustave Roussy Cancer Center, Villejuif, France. (12) Gustave Roussy Cancer Campus (GRCC), Villejuif, France. Institut National de la Sant et de la Recherche Mdicale, U1015, Institut Gustave Roussy, Villejuif, France. (13) Gustave Roussy Cancer Campus (GRCC), Villejuif, France. Institut National de la Sant et de la Recherche Mdicale, U1015, Institut Gustave Roussy, Villejuif, France. Universit Paris-Saclay, Villejuif, F-94805, France. (14) Gustave Roussy Cancer Campus (GRCC), Villejuif, France. Institut National de la Sant et de la Recherche Mdicale, U1015, Institut Gustave Roussy, Villejuif, France. (15) Institut Universitaire de Cardiologie et de Pneumologie de Qubec, Research Center and Department of Cytology and Pathology, Qubec City, Qubec, Canada. (16) Institut Universitaire de Cardiologie et de Pneumologie de Qubec, Research Center and Department of Cytology and Pathology, Qubec City, Qubec, Canada. (17) Institut Universitaire de Cardiologie et de Pneumologie de Qubec, Research Center and Department of Cytology and Pathology, Qubec City, Qubec, Canada. (18) Bacteriophage, Bacterium, Host Laboratory, Institut Pasteur, F-75015 Paris, France. Sorbonne Universit, Centre de Recherche Saint Antoine, INSERM UMRS_938, Paris, France. (19) Bacteriophage, Bacterium, Host Laboratory, Institut Pasteur, F-75015 Paris, France. (20) CRCINA, INSERM, Universit d'Angers, Universit de Nantes, Nantes, France. LabEx IGO "Immunotherapy, Graft, Oncology," Nantes, France. (21) Cancer Research Centre of Toulouse, INSERM UMR 1037, 31037 Toulouse, France; Universit Toulouse III Paul Sabatier, 31330 Toulouse, France; Institut Universitaire du Cancer de Toulouse-Oncopole, 31100 Toulouse, France. (22) Cancer Research Centre of Toulouse, INSERM UMR 1037, 31037 Toulouse, France; Universit Toulouse III Paul Sabatier, 31330 Toulouse, France; Institut Universitaire du Cancer de Toulouse-Oncopole, 31100 Toulouse, France. (23) Unit of Tumor Immunology and Immunotherapy, Department of Research, Advanced Diagnostics and Technological Innovation, IRCCS Regina Elena National Cancer Institute, Rome, Italy. (24) Thoracic Surgery Unit, Department of Surgical Oncology, IRCCS Regina Elena National Cancer Institute, Rome, Italy. (25) Unit of Molecular Biology, Department of Biology and Pathology of Tumors, Georges-Franois Leclerc Anticancer Center, UNICANCER, Dijon, France. (26) Institut Pasteur, Unit Biology and Genetics of the Bacterial Cell Wall, Paris, France. (27) Institut Pasteur, Unit Biology and Genetics of the Bacterial Cell Wall, Paris, France. (28) Computational Health Informatics Program (CHIP), Boston Children's Hospital, Boston, MA, USA. (29) Department of Physics of Complex Systems, ELTE Etvs Lornd University, Budapest, Hungary. (30) Department of Physics of Complex Systems, ELTE Etvs Lornd University, Budapest, Hungary. (31) Department of Agricultural Sciences, University of Naples Federico II, Naples, Italy. (32) Department CIBIO, University of Trento, Trento, Italy. (33) Equipe 11 labellise Ligue contre le Cancer, Centre de Recherche des Cordeliers, Paris, France. INSERM U1138, Paris, France. Universit de Paris, Paris, France. Sorbonne Universit, Paris, France. Departamento de Bioqumica y Biologa Molecular, Instituto Universitario de Oncologa (IUOPA), Universidad de Oviedo, Oviedo, Spain. (34) Computational Health Informatics Program (CHIP), Boston Children's Hospital, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. Danish Cancer Society Research Center, Copenhagen, Denmark. MTA-SE-NAP, Brain Metastasis Research Group, 2nd Department of Pathology, Semmelweis University, Budapest, Hungary. (35) Department of Cancer Medicine, Breast Cancer Committee, Gustave Roussy, Villejuif, France. INSERM Unit 981, Gustave Roussy, Villejuif, France. (36) Gustave Roussy Cancer Campus (GRCC), Villejuif, France. Institut National de la Sant et de la Recherche Mdicale, U1015, Institut Gustave Roussy, Villejuif, France. Department of Medical Sciences, University of Trieste, 34137 Trieste, Italy. (37) AP-HP, Hpital Piti-Salptrire, Clinical Investigation Center in Biotherapy (CIC-BTi) and Immunology-Inflammation-Infectiology and Dermatology Department (3iD), F-75651, Paris, France. Sorbonne Universit, INSERM, Immunology-Immunopathology-Immunotherapy (i3), F-75651, Paris, France. (38) AP-HP, Hpital Piti-Salptrire, Clinical Investigation Center in Biotherapy (CIC-BTi) and Immunology-Inflammation-Infectiology and Dermatology Department (3iD), F-75651, Paris, France. Sorbonne Universit, INSERM, Immunology-Immunopathology-Immunotherapy (i3), F-75651, Paris, France. (39) UMR MEPHI, Aix-Marseille Universit, IRD, AP-HM, Institut Hospitalo-Universitaire Mditerrane-Infection, 19-21 Boulevard Jean Moulin, 13385, Marseille cedex 05, France. (40) UMR MEPHI, Aix-Marseille Universit, IRD, AP-HM, Institut Hospitalo-Universitaire Mditerrane-Infection, 19-21 Boulevard Jean Moulin, 13385, Marseille cedex 05, France. (41) UMR MEPHI, Aix-Marseille Universit, IRD, AP-HM, Institut Hospitalo-Universitaire Mditerrane-Infection, 19-21 Boulevard Jean Moulin, 13385, Marseille cedex 05, France. (42) Gustave Roussy Cancer Campus (GRCC), Villejuif, France. Department of Medical Oncology, Gustave Roussy, Villejuif, France. (43) Gustave Roussy Cancer Campus (GRCC), Villejuif, France. Department of Medical Oncology, Gustave Roussy, Villejuif, France. INSERM U981, GRCC, Villejuif, France. (44) Gustave Roussy Cancer Campus (GRCC), Villejuif, France. Princess Maxima Center, CS 3584 Utrecht, the Netherlands. (45) INSERM UMR 1186, Integrative Tumor Immunology and Immunotherapy, Gustave Roussy, Fac. de Mdecine - Univ. Paris-Sud, Universit Paris-Saclay, 94805, Villejuif, France. (46) Unit of Tumor Immunology and Immunotherapy, Department of Research, Advanced Diagnostics and Technological Innovation, IRCCS Regina Elena National Cancer Institute, Rome, Italy. Thoracic Surgery Unit, Department of Surgical Oncology, IRCCS Regina Elena National Cancer Institute, Rome, Italy. (47) Department of Medical Oncology, Center GF Leclerc, Dijon, France. (48) Institut Universitaire de Cardiologie et de Pneumologie de Qubec, Research Center and Department of Cytology and Pathology, Qubec City, Qubec, Canada. Division d'Hmato-Oncologie, Dpartement de Mdicine, Centre Hospitalier de l'Universit de Montral (CHUM), Montral, Qubec, Canada. (49) CRCINA, INSERM, Universit d'Angers, Universit de Nantes, Nantes, France. LabEx IGO "Immunotherapy, Graft, Oncology," Nantes, France. (50) Universit Rennes 1, Laboratoire de Biochimie Pharmaceutique, Inserm U1230 - UPRES EA 2311, Rennes, France. CHU de Rennes - Hpital Ponchaillou, Service de Bactriologie-Hygine Hospitalire, Rennes, France. CNR de la Rsistance aux Antibiotiques (laboratoire associ 'Entrocoques'), Rennes, France. (51) Cell Biology and Metabolomics Platforms, Gustave Roussy Cancer Campus, Villejuif, France. laurence.zitvogel@gustaveroussy.fr kroemer@orange.fr. Equipe 11 labellise Ligue contre le Cancer, Centre de Recherche des Cordeliers, Paris, France. INSERM U1138, Paris, France. Universit de Paris, Paris, France. Sorbonne Universit, Paris, France. Ple de Biologie, Hpital Europen Georges Pompidou, Assistance Publique-Hpitaux de Paris, Paris, France. Department of Women's and Children's Health, Karolinska University Hospital, 1 Stockholm, Sweden. Suzhou Institute for Systems Biology, Chinese Academy of Medical Sciences, Suzhou, China. Institut Universitaire de France, Paris, France. (52) Gustave Roussy Cancer Campus (GRCC), Villejuif, France. laurence.zitvogel@gustaveroussy.fr kroemer@orange.fr. Institut National de la Sant et de la Recherche Mdicale, U1015, Institut Gustave Roussy, Villejuif, France. Universit Paris-Saclay, Villejuif, F-94805, France. Suzhou Institute for Systems Biology, Chinese Academy of Medical Sciences, Suzhou, China.
