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  • 1
    Abstract: Melanoma prognosis is dictated by tumor-infiltrating lymphocytes, the migratory and functional behavior of which is guided by chemokine or cytokine gradients. Here, we retrospectively analyzed the expression patterns of 9 homing receptors (CCR/CXCR) in naive and memory CD4+ and CD8+ T lymphocytes in 57 patients with metastatic melanoma (MMel) with various sites of metastases to evaluate whether T cell CCR/CXCR expression correlates with intratumoral accumulation, metastatic progression, and/or overall survival (OS). Homing receptor expression on lymphocytes strongly correlated with MMel dissemination. Loss of CCR6 or CXCR3, but not cutaneous lymphocyte antigen (CLA), on circulating T cell subsets was associated with skin or lymph node metastases, loss of CXCR4, CXCR5, and CCR9 corresponded with lung involvement, and a rise in CCR10 or CD103 was associated with widespread dissemination. High frequencies of CD8+CCR9+ naive T cells correlated with prolonged OS, while neutralizing the CCR9/CCL25 axis in mice stimulated tumor progression. The expansion of CLA-expressing effector memory CD8+ T cells in response to a single administration of CTLA4 blockade predicted disease control at 3 months in 47 patients with MMel. Thus, specific CCR/CXCR expression patterns on circulating T lymphocytes may guide potential diagnostic and therapeutic approaches.
    Type of Publication: Journal article published
    PubMed ID: 26854930
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  • 2
    Publication Date: 2018-01-05
    Description: Immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis induce sustained clinical responses in a sizable minority of cancer patients. We found that primary resistance to ICIs can be attributed to abnormal gut microbiome composition. Antibiotics inhibited the clinical benefit of ICIs in patients with advanced cancer. Fecal microbiota transplantation (FMT) from cancer patients who responded to ICIs into germ-free or antibiotic-treated mice ameliorated the antitumor effects of PD-1 blockade, whereas FMT from nonresponding patients failed to do so. Metagenomics of patient stool samples at diagnosis revealed correlations between clinical responses to ICIs and the relative abundance of Akkermansia muciniphila . Oral supplementation with A. muciniphila after FMT with nonresponder feces restored the efficacy of PD-1 blockade in an interleukin-12–dependent manner by increasing the recruitment of CCR9 + CXCR3 + CD4 + T lymphocytes into mouse tumor beds.
    Keywords: Immunology, Medicine, Diseases
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Geosciences , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 3
    Publication Date: 2013-11-23
    Description: Cyclophosphamide is one of several clinically important cancer drugs whose therapeutic efficacy is due in part to their ability to stimulate antitumor immune responses. Studying mouse models, we demonstrate that cyclophosphamide alters the composition of microbiota in the small intestine and induces the translocation of selected species of Gram-positive bacteria into secondary lymphoid organs. There, these bacteria stimulate the generation of a specific subset of "pathogenic" T helper 17 (pT(H)17) cells and memory T(H)1 immune responses. Tumor-bearing mice that were germ-free or that had been treated with antibiotics to kill Gram-positive bacteria showed a reduction in pT(H)17 responses, and their tumors were resistant to cyclophosphamide. Adoptive transfer of pT(H)17 cells partially restored the antitumor efficacy of cyclophosphamide. These results suggest that the gut microbiota help shape the anticancer immune response.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4048947/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4048947/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Viaud, Sophie -- Saccheri, Fabiana -- Mignot, Gregoire -- Yamazaki, Takahiro -- Daillere, Romain -- Hannani, Dalil -- Enot, David P -- Pfirschke, Christina -- Engblom, Camilla -- Pittet, Mikael J -- Schlitzer, Andreas -- Ginhoux, Florent -- Apetoh, Lionel -- Chachaty, Elisabeth -- Woerther, Paul-Louis -- Eberl, Gerard -- Berard, Marion -- Ecobichon, Chantal -- Clermont, Dominique -- Bizet, Chantal -- Gaboriau-Routhiau, Valerie -- Cerf-Bensussan, Nadine -- Opolon, Paule -- Yessaad, Nadia -- Vivier, Eric -- Ryffel, Bernhard -- Elson, Charles O -- Dore, Joel -- Kroemer, Guido -- Lepage, Patricia -- Boneca, Ivo Gomperts -- Ghiringhelli, Francois -- Zitvogel, Laurence -- P01 DK071176/DK/NIDDK NIH HHS/ -- P01DK071176/DK/NIDDK NIH HHS/ -- P50 CA086355/CA/NCI NIH HHS/ -- R01 AI084880/AI/NIAID NIH HHS/ -- New York, N.Y. -- Science. 2013 Nov 22;342(6161):971-6. doi: 10.1126/science.1240537.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institut National de la Sante et de la Recherche Medicale, U1015, Equipe labellisee Ligue Nationale Contre le Cancer, Institut Gustave Roussy, Villejuif, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24264990" target="_blank"〉PubMed〈/a〉
    Keywords: Adoptive Transfer ; Animals ; Anti-Bacterial Agents/administration & dosage ; Antineoplastic Agents/*therapeutic use ; Bacterial Translocation/*drug effects ; Cyclophosphamide/*therapeutic use ; Germ-Free Life ; Gram-Positive Bacteria/drug effects/physiology ; Immunologic Memory ; Immunosuppressive Agents/*therapeutic use ; Intestine, Small/*microbiology ; Lymphoid Tissue/immunology/microbiology ; Mice ; Microbiota/drug effects/*physiology ; Neoplasms/*drug therapy/*immunology ; Th17 Cells/immunology/transplantation
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 4
    Publication Date: 2015-11-07
    Description: Antibodies targeting CTLA-4 have been successfully used as cancer immunotherapy. We find that the antitumor effects of CTLA-4 blockade depend on distinct Bacteroides species. In mice and patients, T cell responses specific for B. thetaiotaomicron or B. fragilis were associated with the efficacy of CTLA-4 blockade. Tumors in antibiotic-treated or germ-free mice did not respond to CTLA blockade. This defect was overcome by gavage with B. fragilis, by immunization with B. fragilis polysaccharides, or by adoptive transfer of B. fragilis-specific T cells. Fecal microbial transplantation from humans to mice confirmed that treatment of melanoma patients with antibodies against CTLA-4 favored the outgrowth of B. fragilis with anticancer properties. This study reveals a key role for Bacteroidales in the immunostimulatory effects of CTLA-4 blockade.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4721659/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4721659/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Vetizou, Marie -- Pitt, Jonathan M -- Daillere, Romain -- Lepage, Patricia -- Waldschmitt, Nadine -- Flament, Caroline -- Rusakiewicz, Sylvie -- Routy, Bertrand -- Roberti, Maria P -- Duong, Connie P M -- Poirier-Colame, Vichnou -- Roux, Antoine -- Becharef, Sonia -- Formenti, Silvia -- Golden, Encouse -- Cording, Sascha -- Eberl, Gerard -- Schlitzer, Andreas -- Ginhoux, Florent -- Mani, Sridhar -- Yamazaki, Takahiro -- Jacquelot, Nicolas -- Enot, David P -- Berard, Marion -- Nigou, Jerome -- Opolon, Paule -- Eggermont, Alexander -- Woerther, Paul-Louis -- Chachaty, Elisabeth -- Chaput, Nathalie -- Robert, Caroline -- Mateus, Christina -- Kroemer, Guido -- Raoult, Didier -- Boneca, Ivo Gomperts -- Carbonnel, Franck -- Chamaillard, Mathias -- Zitvogel, Laurence -- R01 CA161879/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 2015 Nov 27;350(6264):1079-84. doi: 10.1126/science.aad1329. Epub 2015 Nov 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institut de Cancerologie Gustave Roussy Cancer Campus (GRCC), 114 rue Edouard Vaillant, 94805 Villejuif, France. INSERM U1015, GRCC, Villejuif, France. University of Paris Sud XI, Kremlin-Bicetre, France. ; Institut National de la Recherche Agronomique (INRA), Micalis-UMR1319, 78360 Jouy-en-Josas, France. ; University of Lille, CNRS, INSERM, Centre Hospitalier Regional Universitaire de Lille, Institut Pasteur de Lille, U1019, UMR 8204, Centre d'Infection et d'Immunite de Lille (CIIL), F-59000 Lille, France. ; Institut de Cancerologie Gustave Roussy Cancer Campus (GRCC), 114 rue Edouard Vaillant, 94805 Villejuif, France. INSERM U1015, GRCC, Villejuif, France. Center of Clinical Investigations in Biotherapies of Cancer 1428, Villejuif, France. ; Institut de Cancerologie Gustave Roussy Cancer Campus (GRCC), 114 rue Edouard Vaillant, 94805 Villejuif, France. INSERM U1015, GRCC, Villejuif, France. University of Paris Sud XI, Kremlin-Bicetre, France. Center of Clinical Investigations in Biotherapies of Cancer 1428, Villejuif, France. ; Institut de Cancerologie Gustave Roussy Cancer Campus (GRCC), 114 rue Edouard Vaillant, 94805 Villejuif, France. INSERM U1015, GRCC, Villejuif, France. Universite Paris Descartes, Sorbonne Paris Cite, Paris, France. ; Department of Radiation Oncology, New York University, New York, NY, USA. ; Microenvironment and Immunity Unit, Institut Pasteur, Paris, France. ; Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore. ; Department of Genetics and Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA. ; Institut de Cancerologie Gustave Roussy Cancer Campus (GRCC), 114 rue Edouard Vaillant, 94805 Villejuif, France. Universite Paris Descartes, Sorbonne Paris Cite, Paris, France. Metabolomics Platform, GRCC, Villejuif, France. ; Animalerie Centrale, Institut Pasteur, Paris, France. ; Centre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale (IPBS), Toulouse, France. Universite de Toulouse, Universite Paul Sabatier, IPBS, F-31077 Toulouse, France. ; Institut de Cancerologie Gustave Roussy Cancer Campus (GRCC), 114 rue Edouard Vaillant, 94805 Villejuif, France. ; Institut de Cancerologie Gustave Roussy Cancer Campus (GRCC), 114 rue Edouard Vaillant, 94805 Villejuif, France. INSERM U1015, GRCC, Villejuif, France. Department of Medical Oncology, Institut Gustave Roussy, Villejuif, France. ; Service de microbiologie, GRCC, Villejuif, France. ; Institut de Cancerologie Gustave Roussy Cancer Campus (GRCC), 114 rue Edouard Vaillant, 94805 Villejuif, France. Laboratory of Immunomonitoring in Oncology, UMS 3655 CNRS/US 23 INSERM, GRCC, Villejuif, France. ; Institut de Cancerologie Gustave Roussy Cancer Campus (GRCC), 114 rue Edouard Vaillant, 94805 Villejuif, France. Department of Medical Oncology, Institut Gustave Roussy, Villejuif, France. INSERM U981, GRCC, Villejuif, France. ; Institut de Cancerologie Gustave Roussy Cancer Campus (GRCC), 114 rue Edouard Vaillant, 94805 Villejuif, France. Department of Medical Oncology, Institut Gustave Roussy, Villejuif, France. ; Universite Paris Descartes, Sorbonne Paris Cite, Paris, France. Metabolomics Platform, GRCC, Villejuif, France. INSERM U848, Villejuif, France. Equipe 11 Labellisee-Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, INSERM U1138, Paris, France. Pole de Biologie, Hopital Europeen Georges Pompidou, Assistance Publique-Hopitaux de Paris, Paris, France. ; Unite des Rickettsies, Faculte de Medecine, Universite de la Mediterranee, Marseille, France. ; Institut Pasteur, Unit of Biology and Genetics of the Bacterial Cell Wall, Paris, France. INSERM, Equipe Avenir, Paris, France. ; University of Paris Sud XI, Kremlin-Bicetre, France. Gastroenterology Department, Hopital Bicetre, Assistance Publique-Hopitaux de Paris, Paris, France. ; Institut de Cancerologie Gustave Roussy Cancer Campus (GRCC), 114 rue Edouard Vaillant, 94805 Villejuif, France. INSERM U1015, GRCC, Villejuif, France. University of Paris Sud XI, Kremlin-Bicetre, France. Center of Clinical Investigations in Biotherapies of Cancer 1428, Villejuif, France. laurence.zitvogel@gustaveroussy.fr.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26541610" target="_blank"〉PubMed〈/a〉
    Keywords: Adult ; Aged ; Aged, 80 and over ; Animals ; Anti-Bacterial Agents/pharmacology ; Antibodies, Monoclonal/adverse effects/*therapeutic use ; Bacteroides/*immunology ; CTLA-4 Antigen/*antagonists & inhibitors/immunology ; Dysbiosis/immunology ; Fecal Microbiota Transplantation ; Female ; Gastrointestinal Microbiome/drug effects/*immunology ; Germ-Free Life/immunology ; Humans ; Immunologic Memory ; Immunotherapy ; Intestines/immunology/microbiology ; Male ; Melanoma/*therapy ; Mice ; Mice, Inbred C57BL ; Middle Aged ; Skin Neoplasms/*therapy ; T-Lymphocytes/immunology
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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