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1. Correction: Metabolomic analyses of COVID-19 patients unravel stage-dependent and prognostic biomarkers

Author

François-Xavier Danlos, Claudia Grajeda-Iglesias, Sylvère Durand, Allan Sauvat, Mathilde Roumier, Delphine Cantin, Emeline Colomba, Julien Rohmer, Fanny Pommeret, Giulia Baciarello, Christophe Willekens, Marc Vasse, Frank Griscelli, Jean-Eudes Fahrner, Anne-Gaëlle Goubet, Agathe Dubuisson, Lisa Derosa, Nitharsshini Nirmalathasan, Delphine Bredel, Séverine Mouraud, Caroline Pradon, Annabelle Stoclin, Flore Rozenberg, Jérôme Duchemin, Georges Jourdi, Syrine Ellouze, Françoise Levavasseur, Laurence Albigès, Jean-Charles Soria, Fabrice Barlesi, Eric Solary, Fabrice André, Frédéric Pène, Félix Ackerman, Luc Mouthon, Laurence Zitvogel, Aurélien Marabelle, Jean-Marie Michot, Michaela Fontenay, and Guido Kroemer

Subjects
Cytology, QH573-671
Published
2024
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2. Metabolomic analyses of COVID-19 patients unravel stage-dependent and prognostic biomarkers

Author

François-Xavier Danlos, Claudia Grajeda-Iglesias, Sylvère Durand, Allan Sauvat, Mathilde Roumier, Delphine Cantin, Emeline Colomba, Julien Rohmer, Fanny Pommeret, Giulia Baciarello, Christophe Willekens, Marc Vasse, Frank Griscelli, Jean-Eudes Fahrner, Anne-Gaëlle Goubet, Agathe Dubuisson, Lisa Derosa, Nitharsshini Nirmalathasan, Delphine Bredel, Séverine Mouraud, Caroline Pradon, Annabelle Stoclin, Flore Rozenberg, Jérôme Duchemin, Georges Jourdi, Syrine Ellouze, Françoise Levavasseur, Laurence Albigès, Jean-Charles Soria, Fabrice Barlesi, Eric Solary, Fabrice André, Frédéric Pène, Félix Ackerman, Luc Mouthon, Laurence Zitvogel, Aurélien Marabelle, Jean-Marie Michot, Michaela Fontenay, and Guido Kroemer

Subjects
Cytology, QH573-671
Abstract

Abstract The circulating metabolome provides a snapshot of the physiological state of the organism responding to pathogenic challenges. Here we report alterations in the plasma metabolome reflecting the clinical presentation of COVID-19 patients with mild (ambulatory) diseases, moderate disease (radiologically confirmed pneumonitis, hospitalization and oxygen therapy), and critical disease (in intensive care). This analysis revealed major disease- and stage-associated shifts in the metabolome, meaning that at least 77 metabolites including amino acids, lipids, polyamines and sugars, as well as their derivatives, were altered in critical COVID-19 patient’s plasma as compared to mild COVID-19 patients. Among a uniformly moderate cohort of patients who received tocilizumab, only 10 metabolites were different among individuals with a favorable evolution as compared to those who required transfer into the intensive care unit. The elevation of one single metabolite, anthranilic acid, had a poor prognostic value, correlating with the maintenance of high interleukin-10 and -18 levels. Given that products of the kynurenine pathway including anthranilic acid have immunosuppressive properties, we speculate on the therapeutic utility to inhibit the rate-limiting enzymes of this pathway including indoleamine 2,3-dioxygenase and tryptophan 2,3-dioxygenase.

Published
2021
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3. Immune system and intestinal microbiota determine efficacy of androgen deprivation therapy against prostate cancer

Author

Hang Phuong Pham, Douglas G McNeel, Laurence Zitvogel, Corentin Richard, Antoine Toubert, Guido Kroemer, Stéphane Culine, Karim Fizazi, Bertrand Routy, Lisa Derosa, Francesco Asnicar, Nicola Segata, Gladys Ferrere, Florent Ginhoux, Anne-Gaelle Goubet, Safae Terrisse, Kousuke Ueda, Andrew Maltez Thomas, Valentin Quiniou, Cassandra Thelemaque, Garett Dunsmore, Emmanuel Clave, Melissa Gamat-Huber, Satoru Yonekura, Conrad Rauber, Jean-Eudes Fahrner, Eugenie Pizzato, Pierre Ly, Marine Fidelle, Marine Mazzenga, Carolina Alves Costa Silva, Federica Armanini, Federica Pinto, Romain Daillère, Pierre Blanchard, Paule Opolon, and Aymeric Silvin

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Background Prostate cancer (PC) responds to androgen deprivation therapy (ADT) usually in a transient fashion, progressing from hormone-sensitive PC (HSPC) to castration-resistant PC (CRPC). We investigated a mouse model of PC as well as specimens from PC patients to unravel an unsuspected contribution of thymus-derived T lymphocytes and the intestinal microbiota in the efficacy of ADT.Methods Preclinical experiments were performed in PC-bearing mice, immunocompetent or immunodeficient. In parallel, we prospectively included 65 HSPC and CRPC patients (Oncobiotic trial) to analyze their feces and blood specimens.Results In PC-bearing mice, ADT increased thymic cellularity and output. PC implanted in T lymphocyte-depleted or athymic mice responded less efficiently to ADT than in immunocompetent mice. Moreover, depletion of the intestinal microbiota by oral antibiotics reduced the efficacy of ADT. PC reduced the relative abundance of Akkermansia muciniphila in the gut, and this effect was reversed by ADT. Moreover, cohousing of PC-bearing mice with tumor-free mice or oral gavage with Akkermansia improved the efficacy of ADT. This appears to be applicable to PC patients because long-term ADT resulted in an increase of thymic output, as demonstrated by an increase in circulating recent thymic emigrant cells (sjTRECs). Moreover, as compared with HSPC controls, CRPC patients demonstrated a shift in their intestinal microbiota that significantly correlated with sjTRECs. While feces from healthy volunteers restored ADT efficacy, feces from PC patients failed to do so.Conclusions These findings suggest the potential clinical utility of reversing intestinal dysbiosis and repairing acquired immune defects in PC patients.

Published
2022
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4. Immunodynamics of explanted human tumors for immuno‐oncology

Author

Agathe Dubuisson, Jean‐Eudes Fahrner, Anne‐Gaëlle Goubet, Safae Terrisse, Nicolas Voisin, Charles Bayard, Sebastien Lofek, Damien Drubay, Delphine Bredel, Séverine Mouraud, Sandrine Susini, Alexandria Cogdill, Lucas Rebuffet, Elise Ballot, Nicolas Jacquelot, Vincent Thomas de Montpreville, Odile Casiraghi, Camélia Radulescu, Sophie Ferlicot, David J Figueroa, Sapna Yadavilli, Jeremy D Waight, Marc Ballas, Axel Hoos, Thomas Condamine, Bastien Parier, Christophe Gaudillat, Bertrand Routy, François Ghiringhelli, Lisa Derosa, Ingrid Breuskin, Mathieu Rouanne, Fabrice André, Cédric Lebacle, Hervé Baumert, Marie Wislez, Elie Fadel, Isabelle Cremer, Laurence Albiges, Birgit Geoerger, Jean‐Yves Scoazec, Yohann Loriot, Guido Kroemer, Aurélien Marabelle, Mélodie Bonvalet, and Laurence Zitvogel

Subjects
“in sitro” assay, cancer, immune checkpoint inhibitors, immunomonitoring, precision oncology, Medicine (General), R5-920, Genetics, QH426-470
Abstract

Abstract Decision making in immuno‐oncology is pivotal to adapt therapy to the tumor microenvironment (TME) of the patient among the numerous options of monoclonal antibodies or small molecules. Predicting the best combinatorial regimen remains an unmet medical need. Here, we report a multiplex functional and dynamic immuno‐assay based on the capacity of the TME to respond to ex vivo stimulation with twelve immunomodulators including immune checkpoint inhibitors (ICI) in 43 human primary tumors. This "in sitro" (in situ/in vitro) assay has the potential to predict unresponsiveness to anti‐PD‐1 mAbs, and to detect the most appropriate and personalized combinatorial regimen. Prospective clinical trials are awaited to validate this in sitro assay.

Published
2021
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5. Trial Watch: Oncolytic viro-immunotherapy of hematologic and solid tumors

Author

Jonathan G. Pol, Sarah Lévesque, Samuel T. Workenhe, Shashi Gujar, Fabrice Le Boeuf, Derek R. Clements, Jean-Eudes Fahrner, Laetitia Fend, John C. Bell, Karen L. Mossman, Jitka Fucikova, Radek Spisek, Laurence Zitvogel, Guido Kroemer, and Lorenzo Galluzzi

Subjects
cavatak, dnx-2401, hf10, maraba mg1, mv-nis, pexa-vec, reolysin, t-vec, Immunologic diseases. Allergy, RC581-607, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Oncolytic viruses selectively target and kill cancer cells in an immunogenic fashion, thus supporting the establishment of therapeutically relevant tumor-specific immune responses. In 2015, the US Food and Drug Administration (FDA) approved the oncolytic herpes simplex virus T-VEC for use in advanced melanoma patients. Since then, a plethora of trials has been initiated to assess the safety and efficacy of multiple oncolytic viruses in patients affected with various malignancies. Here, we summarize recent preclinical and clinical progress in the field of oncolytic virotherapy.

Published
2018
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6. Genomic Instability and Protumoral Inflammation Are Associated with Primary Resistance to Anti–PD-1 + Antiangiogenesis in Malignant Pleural Mesothelioma

Author

François-Xavier Danlos, Matthieu Texier, Bastien Job, Severine Mouraud, Lydie Cassard, Capucine Baldini, Andrea Varga, Andrey A. Yurchenko, Audrey Rabeau, Stéphane Champiat, Diane Letourneur, Delphine Bredel, Sandrine Susini, Yuna Blum, Aurelien Parpaleix, Cedric Parlavecchio, Lambros Tselikas, Jean-Eudes Fahrner, Anne-Gaelle Goubet, Mathieu Rouanne, Saloomeh Rafie, Alae Abbassi, Ines Kasraoui, Marie Breckler, Siham Farhane, Samy Ammari, Salim Laghouati, Anas Gazzah, Ludovic Lacroix, Benjamin Besse, Nathalie Droin, Marc Deloger, Sophie Cotteret, Julien Adam, Laurence Zitvogel, Sergey I. Nikolaev, Nathalie Chaput, Christophe Massard, Jean-Charles Soria, Carlos Gomez-Roca, Gerard Zalcman, David Planchard, Aurelien Marabelle, 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, École normale supérieure de Lyon (ENS de Lyon), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Département d'imagerie médicale [Gustave Roussy], Département de biologie et pathologie médicales [Gustave Roussy], Département de médecine oncologique, CRLCC Paul Strauss, Dynamique moléculaire de la transformation hématopoïétique (Dynamo), Département de médecine oncologique [Gustave Roussy], Prédicteurs moléculaires et nouvelles cibles en oncologie (PMNCO), Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse (AMMICa), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Département d’Innovation Thérapeutique et essais précoces [Gustave Roussy] (DITEP), and Institut Claudius Regaud

Subjects
Oncology, [SDV.CAN]Life Sciences [q-bio]/Cancer
Abstract

Cancer immunotherapy combinations have recently been shown to improve the overall survival of advanced mesotheliomas, especially for patients responding to those treatments. We aimed to characterize the biological correlates of malignant pleural mesotheliomas’ primary resistance to immunotherapy and antiangiogenics by testing the combination of pembrolizumab, an anti–PD-1 antibody, and nintedanib, a pan-antiangiogenic tyrosine kinase inhibitor, in the multicenter PEMBIB trial (NCT02856425). Thirty patients with advanced malignant pleural mesothelioma were treated and explored. Unexpectedly, we found that refractory patients were actively recruiting CD3+CD8+ cytotoxic T cells in their tumors through CXCL9 tumor release upon treatment. However, these patients displayed high levels of somatic copy-number alterations in their tumors that correlated with high blood and tumor levels of IL6 and CXCL8. Those proinflammatory cytokines resulted in higher tumor secretion of VEGF and tumor enrichment in regulatory T cells. Advanced mesothelioma should further benefit from stratified combination therapies adapted to their tumor biology. Significance: Sequential explorations of fresh tumor biopsies demonstrated that mesothelioma resistance to anti–PD-1 + antiangiogenics is not due to a lack of tumor T-cell infiltration but rather due to adaptive immunosuppressive pathways by tumors, involving molecules (e.g., IL6, CXCL8, VEGF, and CTLA4) that are amenable to targeted therapies. This article is highlighted in the In This Issue feature, p. 799

Published
2023

7. Supplementary Table S5 from Genomic Instability and Protumoral Inflammation Are Associated with Primary Resistance to Anti–PD-1 + Antiangiogenesis in Malignant Pleural Mesothelioma

Author

Aurelien Marabelle, David Planchard, Gerard Zalcman, Carlos Gomez-Roca, Jean-Charles Soria, Christophe Massard, Nathalie Chaput, Sergey I. Nikolaev, Laurence Zitvogel, Julien Adam, Sophie Cotteret, Marc Deloger, Nathalie Droin, Benjamin Besse, Ludovic Lacroix, Anas Gazzah, Salim Laghouati, Samy Ammari, Siham Farhane, Marie Breckler, Ines Kasraoui, Alae Abbassi, Saloomeh Rafie, Mathieu Rouanne, Anne-Gaelle Goubet, Jean-Eudes Fahrner, Lambros Tselikas, Cedric Parlavecchio, Aurelien Parpaleix, Yuna Blum, Sandrine Susini, Delphine Bredel, Diane Letourneur, Stéphane Champiat, Audrey Rabeau, Andrey A. Yurchenko, Andrea Varga, Capucine Baldini, Lydie Cassard, Severine Mouraud, Bastien Job, Matthieu Texier, and François-Xavier Danlos

Abstract

Immuno-Histo-Chemistry scoring of baseline tumor biopsies according to their DCB status.

Published
2023

8. Supplementary Figure from Cancer Induces a Stress Ileopathy Depending on β-Adrenergic Receptors and Promoting Dysbiosis that Contributes to Carcinogenesis

Author

Laurence Zitvogel, Lisa Derosa, Edoardo Pasolli, Jean-Yves Scoazec, Hans Clevers, Fjodor Yousef Yengej, Nicola Segata, Mohamed-Amine Bani, Leonardo Lordello, Bertrand Routy, Guido Kroemer, Oliver Kepp, Bernhard Ryffel, Sylvie Berrard, Valentin Quiniou, Sophie Ugolini, Connie P.M. Duong, Paul Hofman, Jacques Bosq, Tamara Matysiak-Budnik, Laetitia Aymeric, Anne Bessard, Michel Neunlist, Fanny Mann, Angélique Puget, Paule Opolon, Nathalie Droin, Marine Aglave, Marc Deloger, Jérôme Cartry, Fanny Jaulin, Marine Fidelle, Cassandra Thelemaque, Marine Mazzenga, Pierre Ly, Eugénie Pizzato, Gibrail Mansouri, Kousuke Ueda, Imran Lahmar, Jean-Eudes Fahrner, Anne-Gaëlle Goubet, Gladys Ferrere, Valerio Iebba, Antoine Lafarge, Carolina Alves Costa Silva, Safae Terrisse, and Satoru Yonekura

Abstract

Supplementary Figure from Cancer Induces a Stress Ileopathy Depending on β-Adrenergic Receptors and Promoting Dysbiosis that Contributes to Carcinogenesis

Published
2023

9. Supplementary Figure from The Polarity and Specificity of Antiviral T Lymphocyte Responses Determine Susceptibility to SARS-CoV-2 Infection in Patients with Cancer and Healthy Individuals

Author

Laurence Zitvogel, Lisa Derosa, Markus Maeurer, Bernard La Scola, Guido Kroemer, Odile Launay, Emma Guttman-Yassky, Florence Fenollar, Sophie Caillat-Zucman, Mathieu F. Chevalier, Juliette Villemonteix, Fabrice André, Miriam Merad, Jean-Charles Soria, Jean-Yves Blay, Frank Griscelli, Aurélien Marabelle, Florian Scotté, Mansouria Merad, Jean-Philippe Spano, Bertrand Gachot, Eric Deutsch, Nathalie Droin, Marc Deloger, Pernelle Lavaud, Emeline Colomba, Fanny Pommeret, Emmanuelle Gallois, Caroline Pradon, Yeriel Estrada, Benjamin Ungar, Alexandre Trubert, Fabrice Barlesi, Guy Gorochov, Makoto Miyara, Abdelhakim Ahmed-Belkacem, Lydia Meziani, Nadine Benhamouda, Eric Tartour, Pierre Ly, Caroline Flament, Eugenie Pizzato, Safae Terrisse, François-Xavier Danlos, Marianne Gazzano, Benoît Kloeckner, Alice Bernard-Tessier, Ariane Laparra, Joana R. Lérias, Luigi Cerbone, Marion Picard, Camille Bigenwald, Roxanne Birebent, Gladys Ferrere, Arthur Geraud, Agathe Dubuisson, Cléa Melenotte, Cassandra Thelemaque, Eric de Sousa, Carolina Alves Costa Silva, Damien Drubay, Marine Mazzenga, Agathe Carrier, Yacine Haddad, Anne-Gaëlle Goubet, Imran Lahmar, and Jean-Eudes Fahrner

Abstract

Supplementary Figure from The Polarity and Specificity of Antiviral T Lymphocyte Responses Determine Susceptibility to SARS-CoV-2 Infection in Patients with Cancer and Healthy Individuals

Published
2023

10. Data from Cancer Induces a Stress Ileopathy Depending on β-Adrenergic Receptors and Promoting Dysbiosis that Contributes to Carcinogenesis

Author

Laurence Zitvogel, Lisa Derosa, Edoardo Pasolli, Jean-Yves Scoazec, Hans Clevers, Fjodor Yousef Yengej, Nicola Segata, Mohamed-Amine Bani, Leonardo Lordello, Bertrand Routy, Guido Kroemer, Oliver Kepp, Bernhard Ryffel, Sylvie Berrard, Valentin Quiniou, Sophie Ugolini, Connie P.M. Duong, Paul Hofman, Jacques Bosq, Tamara Matysiak-Budnik, Laetitia Aymeric, Anne Bessard, Michel Neunlist, Fanny Mann, Angélique Puget, Paule Opolon, Nathalie Droin, Marine Aglave, Marc Deloger, Jérôme Cartry, Fanny Jaulin, Marine Fidelle, Cassandra Thelemaque, Marine Mazzenga, Pierre Ly, Eugénie Pizzato, Gibrail Mansouri, Kousuke Ueda, Imran Lahmar, Jean-Eudes Fahrner, Anne-Gaëlle Goubet, Gladys Ferrere, Valerio Iebba, Antoine Lafarge, Carolina Alves Costa Silva, Safae Terrisse, and Satoru Yonekura

Abstract

Gut dysbiosis has been associated with intestinal and extraintestinal malignancies, but whether and how carcinogenesis drives compositional shifts of the microbiome to its own benefit remains an open conundrum. Here, we show that malignant processes can cause ileal mucosa atrophy, with villous microvascular constriction associated with dominance of sympathetic over cholinergic signaling. The rapid onset of tumorigenesis induced a burst of REG3γ release by ileal cells, and transient epithelial barrier permeability that culminated in overt and long-lasting dysbiosis dominated by Gram-positive Clostridium species. Pharmacologic blockade of β-adrenergic receptors or genetic deficiency in Adrb2 gene, vancomycin, or cohousing of tumor bearers with tumor-free littermates prevented cancer-induced ileopathy, eventually slowing tumor growth kinetics. Patients with cancer harbor distinct hallmarks of this stress ileopathy dominated by Clostridium species. Hence, stress ileopathy is a corollary disease of extraintestinal malignancies requiring specific therapies.Significance:Whether gut dysbiosis promotes tumorigenesis and how it controls tumor progression remain open questions. We show that 50% of transplantable extraintestinal malignancies triggered a β-adrenergic receptor–dependent ileal mucosa atrophy, associated with increased gut permeability, sustained Clostridium spp.–related dysbiosis, and cancer growth. Vancomycin or propranolol prevented cancer-associated stress ileopathy.This article is highlighted in the In This Issue feature, p. 873

Published
2023

11. Supplementary Data from The Polarity and Specificity of Antiviral T Lymphocyte Responses Determine Susceptibility to SARS-CoV-2 Infection in Patients with Cancer and Healthy Individuals

Author

Laurence Zitvogel, Lisa Derosa, Markus Maeurer, Bernard La Scola, Guido Kroemer, Odile Launay, Emma Guttman-Yassky, Florence Fenollar, Sophie Caillat-Zucman, Mathieu F. Chevalier, Juliette Villemonteix, Fabrice André, Miriam Merad, Jean-Charles Soria, Jean-Yves Blay, Frank Griscelli, Aurélien Marabelle, Florian Scotté, Mansouria Merad, Jean-Philippe Spano, Bertrand Gachot, Eric Deutsch, Nathalie Droin, Marc Deloger, Pernelle Lavaud, Emeline Colomba, Fanny Pommeret, Emmanuelle Gallois, Caroline Pradon, Yeriel Estrada, Benjamin Ungar, Alexandre Trubert, Fabrice Barlesi, Guy Gorochov, Makoto Miyara, Abdelhakim Ahmed-Belkacem, Lydia Meziani, Nadine Benhamouda, Eric Tartour, Pierre Ly, Caroline Flament, Eugenie Pizzato, Safae Terrisse, François-Xavier Danlos, Marianne Gazzano, Benoît Kloeckner, Alice Bernard-Tessier, Ariane Laparra, Joana R. Lérias, Luigi Cerbone, Marion Picard, Camille Bigenwald, Roxanne Birebent, Gladys Ferrere, Arthur Geraud, Agathe Dubuisson, Cléa Melenotte, Cassandra Thelemaque, Eric de Sousa, Carolina Alves Costa Silva, Damien Drubay, Marine Mazzenga, Agathe Carrier, Yacine Haddad, Anne-Gaëlle Goubet, Imran Lahmar, and Jean-Eudes Fahrner

Abstract

Supplementary Data from The Polarity and Specificity of Antiviral T Lymphocyte Responses Determine Susceptibility to SARS-CoV-2 Infection in Patients with Cancer and Healthy Individuals

Published
2023

12. Supplementary Figure S6 from Genomic Instability and Protumoral Inflammation Are Associated with Primary Resistance to Anti–PD-1 + Antiangiogenesis in Malignant Pleural Mesothelioma

Author

Aurelien Marabelle, David Planchard, Gerard Zalcman, Carlos Gomez-Roca, Jean-Charles Soria, Christophe Massard, Nathalie Chaput, Sergey I. Nikolaev, Laurence Zitvogel, Julien Adam, Sophie Cotteret, Marc Deloger, Nathalie Droin, Benjamin Besse, Ludovic Lacroix, Anas Gazzah, Salim Laghouati, Samy Ammari, Siham Farhane, Marie Breckler, Ines Kasraoui, Alae Abbassi, Saloomeh Rafie, Mathieu Rouanne, Anne-Gaelle Goubet, Jean-Eudes Fahrner, Lambros Tselikas, Cedric Parlavecchio, Aurelien Parpaleix, Yuna Blum, Sandrine Susini, Delphine Bredel, Diane Letourneur, Stéphane Champiat, Audrey Rabeau, Andrey A. Yurchenko, Andrea Varga, Capucine Baldini, Lydie Cassard, Severine Mouraud, Bastien Job, Matthieu Texier, and François-Xavier Danlos

Abstract

Cytotoxic response in tumor biopsies of patients with No DCB upon combination treatment.

Published
2023

13. Data from The Polarity and Specificity of Antiviral T Lymphocyte Responses Determine Susceptibility to SARS-CoV-2 Infection in Patients with Cancer and Healthy Individuals

Author

Laurence Zitvogel, Lisa Derosa, Markus Maeurer, Bernard La Scola, Guido Kroemer, Odile Launay, Emma Guttman-Yassky, Florence Fenollar, Sophie Caillat-Zucman, Mathieu F. Chevalier, Juliette Villemonteix, Fabrice André, Miriam Merad, Jean-Charles Soria, Jean-Yves Blay, Frank Griscelli, Aurélien Marabelle, Florian Scotté, Mansouria Merad, Jean-Philippe Spano, Bertrand Gachot, Eric Deutsch, Nathalie Droin, Marc Deloger, Pernelle Lavaud, Emeline Colomba, Fanny Pommeret, Emmanuelle Gallois, Caroline Pradon, Yeriel Estrada, Benjamin Ungar, Alexandre Trubert, Fabrice Barlesi, Guy Gorochov, Makoto Miyara, Abdelhakim Ahmed-Belkacem, Lydia Meziani, Nadine Benhamouda, Eric Tartour, Pierre Ly, Caroline Flament, Eugenie Pizzato, Safae Terrisse, François-Xavier Danlos, Marianne Gazzano, Benoît Kloeckner, Alice Bernard-Tessier, Ariane Laparra, Joana R. Lérias, Luigi Cerbone, Marion Picard, Camille Bigenwald, Roxanne Birebent, Gladys Ferrere, Arthur Geraud, Agathe Dubuisson, Cléa Melenotte, Cassandra Thelemaque, Eric de Sousa, Carolina Alves Costa Silva, Damien Drubay, Marine Mazzenga, Agathe Carrier, Yacine Haddad, Anne-Gaëlle Goubet, Imran Lahmar, and Jean-Eudes Fahrner

Abstract

Vaccination against coronavirus disease 2019 (COVID-19) relies on the in-depth understanding of protective immune responses to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). We characterized the polarity and specificity of memory T cells directed against SARS-CoV-2 viral lysates and peptides to determine correlates with spontaneous, virus-elicited, or vaccine-induced protection against COVID-19 in disease-free and cancer-bearing individuals. A disbalance between type 1 and 2 cytokine release was associated with high susceptibility to COVID-19. Individuals susceptible to infection exhibited a specific deficit in the T helper 1/T cytotoxic 1 (Th1/Tc1) peptide repertoire affecting the receptor binding domain of the spike protein (S1-RBD), a hotspot of viral mutations. Current vaccines triggered Th1/Tc1 responses in only a fraction of all subject categories, more effectively against the original sequence of S1-RBD than that from viral variants. We speculate that the next generation of vaccines should elicit Th1/Tc1 T-cell responses against the S1-RBD domain of emerging viral variants.Significance:This study prospectively analyzed virus-specific T-cell correlates of protection against COVID-19 in healthy and cancer-bearing individuals. A disbalance between Th1/Th2 recall responses conferred susceptibility to COVID-19 in both populations, coinciding with selective defects in Th1 recognition of the receptor binding domain of spike.See related commentary by McGary and Vardhana, p. 892.This article is highlighted in the In This Issue feature, p. 873

Published
2023

14. Data from Genomic Instability and Protumoral Inflammation Are Associated with Primary Resistance to Anti–PD-1 + Antiangiogenesis in Malignant Pleural Mesothelioma

Author

Aurelien Marabelle, David Planchard, Gerard Zalcman, Carlos Gomez-Roca, Jean-Charles Soria, Christophe Massard, Nathalie Chaput, Sergey I. Nikolaev, Laurence Zitvogel, Julien Adam, Sophie Cotteret, Marc Deloger, Nathalie Droin, Benjamin Besse, Ludovic Lacroix, Anas Gazzah, Salim Laghouati, Samy Ammari, Siham Farhane, Marie Breckler, Ines Kasraoui, Alae Abbassi, Saloomeh Rafie, Mathieu Rouanne, Anne-Gaelle Goubet, Jean-Eudes Fahrner, Lambros Tselikas, Cedric Parlavecchio, Aurelien Parpaleix, Yuna Blum, Sandrine Susini, Delphine Bredel, Diane Letourneur, Stéphane Champiat, Audrey Rabeau, Andrey A. Yurchenko, Andrea Varga, Capucine Baldini, Lydie Cassard, Severine Mouraud, Bastien Job, Matthieu Texier, and François-Xavier Danlos

Abstract

Cancer immunotherapy combinations have recently been shown to improve the overall survival of advanced mesotheliomas, especially for patients responding to those treatments. We aimed to characterize the biological correlates of malignant pleural mesotheliomas’ primary resistance to immunotherapy and antiangiogenics by testing the combination of pembrolizumab, an anti–PD-1 antibody, and nintedanib, a pan-antiangiogenic tyrosine kinase inhibitor, in the multicenter PEMBIB trial (NCT02856425). Thirty patients with advanced malignant pleural mesothelioma were treated and explored. Unexpectedly, we found that refractory patients were actively recruiting CD3+CD8+ cytotoxic T cells in their tumors through CXCL9 tumor release upon treatment. However, these patients displayed high levels of somatic copy-number alterations in their tumors that correlated with high blood and tumor levels of IL6 and CXCL8. Those proinflammatory cytokines resulted in higher tumor secretion of VEGF and tumor enrichment in regulatory T cells. Advanced mesothelioma should further benefit from stratified combination therapies adapted to their tumor biology.Significance:Sequential explorations of fresh tumor biopsies demonstrated that mesothelioma resistance to anti–PD-1 + antiangiogenics is not due to a lack of tumor T-cell infiltration but rather due to adaptive immunosuppressive pathways by tumors, involving molecules (e.g., IL6, CXCL8, VEGF, and CTLA4) that are amenable to targeted therapies.This article is highlighted in the In This Issue feature, p. 799

Published
2023

15. Cancer induces a stress ileopathy depending on B-adrenergic receptors and promoting dysbiosis that contribute to carcinogenesis

Author

Satoru Yonekura, Safae Terrisse, Carolina Alves Costa Silva, Antoine Lafarge, Valerio Iebba, Gladys Ferrere, Anne-Gaëlle Goubet, Jean-Eudes Fahrner, Imran Lahmar, Kousuke Ueda, Gibrail Mansouri, Eugénie Pizzato, Pierre Ly, Marine Mazzenga, Cassandra Thelemaque, Marine Fidelle, Fanny Jaulin, Jérôme Cartry, Marc Deloger, Marine Aglave, Nathalie Droin, Paule Opolon, Angélique Puget, Fanny Mann, Michel Neunlist, Anne Bessard, Laetitia Aymeric, Tamara Matysiak-Budnik, Jacques Bosq, Paul Hofman, Connie P.M. Duong, Sophie Ugolini, Valentin Quiniou, Sylvie Berrard, Bernhard Ryffel, Oliver Kepp, Guido Kroemer, Bertrand Routy, Leonardo Lordello, Mohamed-Amine Bani, Nicola Segata, Fjodor Yousef Yengej, Hans Clevers, Jean-Yves Scoazec, Edoardo Pasolli, Lisa Derosa, Laurence Zitvogel, Hubrecht Institute for Developmental Biology and Stem Cell Research, Yonekura, Satoru, Terrisse, Safae, Alves Costa Silva, Carolina, Lafarge, Antoine, Iebba, Valerio, Ferrere, Glady, Goubet, Anne-Gaelle, Fahrner, Jean-Eude, Lahmar, Imran, Ueda, Kosuke, Mansouri, Gibrail, Pizzato, Eugenie, Ly, Pierre, Mazzenga, Marine, Thelemaque, Cassandra, Fidelle, Marine, Jaulin, Fanny, Cartry, Jerome, Deloger, Marc, Aglave, Marine, Droin, Nathalie, Opolon, Paule, Puget, Angelique, Mann, Fanny, Neunlist, Michel, Bessard, Anne, Aymeric, Laetitia, Matysiak-Budnik, Tamara, Bosq, Jacque, Hofman, Paul, Duong, Connie P M, Ugolini, Sophie, Quiniou, Valentin, Berrard, Sylvie, Ryffel, Bernhard, Kepp, Oliver, Kroemer, Guido, Routy, Bertrand, Lordello, Leonardo, Bani, Mohamed-Amine, Segata, Nicola, Yousef Yengej, Fjodor, Clevers, Han, Scoazec, Jean-Yve, Pasolli, Edoardo, Derosa, Lisa, Zitvogel, Laurence, Institut de Biologie du Développement de Marseille (IBDM), and Aix Marseille Université (AMU)-Collège de France (CdF (institution))-Centre National de la Recherche Scientifique (CNRS)

Subjects
metagenomics, bioinformatic, Carcinogenesis, [SDV]Life Sciences [q-bio], microbiome, bioinformatics, Gut dysbiosi, B-adrenergic receptors, Gut dysbiosis, Oncology, epithelial barrier permeability, chemiotherapy, Receptors, Adrenergic, beta, microbiota, carcinogenesis, stress ileopathy, immunotherapy, Dysbiosis, Humans, carcinogenesi, Intestinal Mucosa, metagenomic, B-adrenergic receptor, Signal Transduction
Abstract

Gut dysbiosis has been associated with intestinal and extraintestinal malignancies, but whether and how carcinogenesis drives compositional shifts of the microbiome to its own benefit remains an open conundrum. Here, we show that malignant processes can cause ileal mucosa atrophy, with villous microvascular constriction associated with dominance of sympathetic over cholinergic signaling. The rapid onset of tumorigenesis induced a burst of REG3γ release by ileal cells, and transient epithelial barrier permeability that culminated in overt and long-lasting dysbiosis dominated by Gram-positive Clostridium species. Pharmacologic blockade of β-adrenergic receptors or genetic deficiency in Adrb2 gene, vancomycin, or cohousing of tumor bearers with tumor-free littermates prevented cancer-induced ileopathy, eventually slowing tumor growth kinetics. Patients with cancer harbor distinct hallmarks of this stress ileopathy dominated by Clostridium species. Hence, stress ileopathy is a corollary disease of extraintestinal malignancies requiring specific therapies. Significance: Whether gut dysbiosis promotes tumorigenesis and how it controls tumor progression remain open questions. We show that 50% of transplantable extraintestinal malignancies triggered a β-adrenergic receptor–dependent ileal mucosa atrophy, associated with increased gut permeability, sustained Clostridium spp.–related dysbiosis, and cancer growth. Vancomycin or propranolol prevented cancer-associated stress ileopathy. This article is highlighted in the In This Issue feature, p. 873

Published
2022

16. The Polarity and Specificity of Antiviral T Lymphocyte Responses Determine Susceptibility to SARS-CoV-2 Infection in Patients with Cancer and Healthy Individuals

Author

Jean-Eudes, Fahrner, Imran, Lahmar, Anne-Gaëlle, Goubet, Yacine, Haddad, Agathe, Carrier, Marine, Mazzenga, Damien, Drubay, Carolina, Alves Costa Silva, Eric, de Sousa, Cassandra, Thelemaque, Cléa, Melenotte, Agathe, Dubuisson, Arthur, Geraud, Gladys, Ferrere, Roxanne, Birebent, Camille, Bigenwald, Marion, Picard, Luigi, Cerbone, Joana R, Lérias, Ariane, Laparra, Alice, Bernard-Tessier, Benoît, Kloeckner, Marianne, Gazzano, François-Xavier, Danlos, Safae, Terrisse, Eugenie, Pizzato, Caroline, Flament, Pierre, Ly, Eric, Tartour, Nadine, Benhamouda, Lydia, Meziani, Abdelhakim, Ahmed-Belkacem, Makoto, Miyara, Guy, Gorochov, Fabrice, Barlesi, Alexandre, Trubert, Benjamin, Ungar, Yeriel, Estrada, Caroline, Pradon, Emmanuelle, Gallois, Fanny, Pommeret, Emeline, Colomba, Pernelle, Lavaud, Marc, Deloger, Nathalie, Droin, Eric, Deutsch, Bertrand, Gachot, Jean-Philippe, Spano, Mansouria, Merad, Florian, Scotté, Aurélien, Marabelle, Frank, Griscelli, Jean-Yves, Blay, Jean-Charles, Soria, Miriam, Merad, Fabrice, André, Juliette, Villemonteix, Mathieu F, Chevalier, Sophie, Caillat-Zucman, Florence, Fenollar, Emma, Guttman-Yassky, Odile, Launay, Guido, Kroemer, Bernard, La Scola, Markus, Maeurer, Lisa, Derosa, Laurence, Zitvogel, Université Paris-Saclay, Vecteurs - Infections tropicales et méditerranéennes (VITROME), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut de Recherche Biomédicale des Armées [Brétigny-sur-Orge] (IRBA), Institut Hospitalier Universitaire Méditerranée Infection (IHU Marseille), Microbes évolution phylogénie et infections (MEPHI), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), AP-HP. Université Paris Saclay, Prédicteurs moléculaires et nouvelles cibles en oncologie (PMNCO), and Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay

Subjects
[SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, SARS-CoV-2, T-Lymphocytes, COVID-19, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Antibodies, Neutralizing, Antiviral Restriction Factors, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Oncology, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Neoplasms, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Spike Glycoprotein, Coronavirus, Humans, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology
Abstract

Vaccination against coronavirus disease 2019 (COVID-19) relies on the in-depth understanding of protective immune responses to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). We characterized the polarity and specificity of memory T cells directed against SARS-CoV-2 viral lysates and peptides to determine correlates with spontaneous, virus-elicited, or vaccine-induced protection against COVID-19 in disease-free and cancer-bearing individuals. A disbalance between type 1 and 2 cytokine release was associated with high susceptibility to COVID-19. Individuals susceptible to infection exhibited a specific deficit in the T helper 1/T cytotoxic 1 (Th1/Tc1) peptide repertoire affecting the receptor binding domain of the spike protein (S1-RBD), a hotspot of viral mutations. Current vaccines triggered Th1/Tc1 responses in only a fraction of all subject categories, more effectively against the original sequence of S1-RBD than that from viral variants. We speculate that the next generation of vaccines should elicit Th1/Tc1 T-cell responses against the S1-RBD domain of emerging viral variants. Significance: This study prospectively analyzed virus-specific T-cell correlates of protection against COVID-19 in healthy and cancer-bearing individuals. A disbalance between Th1/Th2 recall responses conferred susceptibility to COVID-19 in both populations, coinciding with selective defects in Th1 recognition of the receptor binding domain of spike. See related commentary by McGary and Vardhana, p. 892. This article is highlighted in the In This Issue feature, p. 873

Published
2021

17. The polarity and specificity of SARS-CoV2-specific T lymphocyte responses determine disease susceptibility

Author

Jean-Yves Blay, Cléa Melenotte, Fabrice Andre, Caroline Pradon, Agathe Carrier, Lydia Meziani, Guy Gorochov, Markus Maeurer, Carolina Alves Costa Silva, Safae Terrisse, Aurélien Marabelle, L. Cerbone, Eric De Sousa, Lisa Derosa, Joana R. Lérias, François-Xavier Danlos, Fanny Pommeret, Yacine Haddad, Florence Fenollar, Bertrand Gachot, Alice Bernard, Caroline Flament, Marianne Gazzano, Benoît Kloeckner, Florian Scotté, Anne-Gaëlle Goubet, Agathe Dubuisson, Cassandra Thelemaque, Eugenie Pizzato, Sophie Caillat-Zucman, Arthur Geraud, Fabrice Barlesi, Marine Mazzenga, Frank Griscelli, Mathieu F. Chevalier, Laurence Zitvogel, Bernard La Scola, Damien Drubay, Abdelhakim Ahmed-Belkacem, Pernelle Lavaud, Emeline Colomba, Jean-Eudes Fahrner, Gladys Ferrere, Eric Tartour, Pierre Ly, Marion Picard, Ariane Laparra, Jean-Philippe Spano, Makoto Miyara, Eric Deutsch, Mansouria Merad, Jean-Charles Soria, Imran Lahmar, Guido Kroemer, and Emmanuelle Gallois

Subjects
viruses, medicine.medical_treatment, T cell, Immunotherapy, T lymphocyte, Biology, medicine.disease_cause, Virus, Immune system, Cytokine, medicine.anatomical_structure, Immunization, Immunology, medicine, Coronavirus
Abstract

Optimal vaccination and immunotherapy against coronavirus disease COVID-19 relies on the in-depth comprehension of immune responses determining the individual susceptibility to be infected by SARS-CoV-2 and to develop severe disease. We characterized the polarity and specificity of circulating SARS-CoV-2-specific T cell responses against whole virus lysates or 186 unique peptides derived from the SARS-CoV-2 or SARS-CoV-1 ORFeome on 296 cancer-bearing and 86 cancer-free individuals who were either from the pre-COVID-19 era (67 individuals) or contemporary COVID-19-free (237 individuals) or who developed COVID-19 (78 individuals) in 2020/21. The ratio between the prototypic T helper 1 (TH1) cytokine, interleukin-2, and the prototypic T helper 2 (TH2) cytokine, interleukin-5 (IL-5), released from SARS-CoV-2-specific memory T cells measured in early 2020, among SARS-CoV-2-negative persons, was associated with the susceptibility of these individuals to develop PCR-detectable SARS-CoV-2 infection in late 2020 or 2021. Of note, T cells from individuals who recovered after SARS-CoV-2 re-infection spontaneously produced elevated levels of IL-5 and secreted the immunosuppressive TH2 cytokine interleukin-10 in response to SARS-CoV-2 lysate, suggesting that TH2 responses to SARS-CoV-2 are inadequate. Moreover, individuals susceptible to SARS-CoV-2 infection exhibited a deficit in the TH1 peptide repertoire affecting the highly mutated receptor binding domain (RBD) amino acids (331-525) of the spike protein. Finally, current vaccines successfully triggered anti-RBD specific TH1 responses in 88% healthy subjects that were negative prior to immunization. These findings indicate that COVID-19 protection relies on TH1 cell immunity against SARS-CoV-2 S1-RBD which in turn likely drives the phylogenetic escape of the virus. The next generation of COVID-19 vaccines should elicit high-avidity TH1 (rather than TH2)-like T cell responses against the RBD domain of current and emerging viral variants.

Published
2021

18. Prolonged SARS-CoV-2 RNA virus shedding and lymphopenia are hallmarks of COVID-19 in cancer patients with poor prognosis

Author

Alain Roulet, Nitharsshini Nirmalathasan, Annabelle Stoclin, Michaela Fontenay, Guy Gorochov, Eric Deutsch, Cléa Melenotte, Lisa Derosa, Gabriel Garcia, Mansouria Merad, Aurelien Marabelle, Benjamin Lelouvier, Eugenie Pizzato, Souad Assaad, Guido Kroemer, Oliver Kepp, Stéphanie Gentile, François-Xavier Danlos, Abdelhakim Ahmed-Belkacem, Jean-Yves Blay, Lydia Meziani, Nadia Saidani, Anne-Gaëlle Goubet, Fanny Pommeret, Carolina Alves Costa Silva, Aymeric Silvin, Bertrand Gachot, Florent Ginhoux, Fabrice Andre, Didier Raoult, Emmanuelle Gallois, Yacine Haddad, Arthur Geraud, Sébastien Cortaredona, Cassandra Thelemaque, Lea Touri, Gladys Ferrere, Sylvère Durand, Emeline Colomba, Corinne Balleyguier, Eric Solary, Bernard La Scola, Damien Drubay, Claudia Grajeda-Iglesias, Frank Griscelli, Anne Florin, Suzanne Kazandjian, Laurence Albiges, Markus Maeurer, Garett Dunsmore, Fabrice Barlesi, Makoto Miyara, Mauro Piacentini, Pierre Ly, Marion Picard, Nathalie Lassau, Caroline Flament, Florian Scotté, Agathe Dubuisson, Giuseppe Ippolito, Safae Terrisse, Jean-Eudes Fahrner, Arielle Elkrief, Bertrand Routy, Marine Mazzenga, Laurence Zitvogel, Caroline Pradon, Imran Lahmar, Jean-Charles Soria, and Fanny Aprahamian

Subjects
biology, business.industry, Lymphocyte, Cancer, RNA virus, medicine.disease_cause, biology.organism_classification, medicine.disease, Granzyme B, medicine.anatomical_structure, Immunopathology, Immunology, medicine, biology.protein, Antibody, business, CD8, Coronavirus
Abstract

Patients with cancer are at higher risk of severe coronavirus infectious disease 2019 (COVID-19), but the mechanisms underlying virus-host interactions during cancer therapies remain elusive. When comparing nasopharyngeal swabs from cancer and non-cancer patients for RT-qPCR cycle thresholds measuring acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in 1063 patients (58% with cancer, 89% COVID-19+), we found that malignant disease favors the magnitude and duration of viral RNA shedding concomitant with prolonged serum elevations of type 1 IFN that anticorrelated with anti-RBD IgG antibodies. Chronic viral RNA carriers exhibited the typical immunopathology of severe COVID-19 at the early phase of infection including circulation of immature neutrophils, depletion of non-conventional monocytes and a general lymphopenia that, however, was accompanied by a rise in plasmablasts, activated follicular T helper cells, and non-naive Granzyme B+ FasL+, EomehighTCF-1high, PD-1+CD8+ Tc1 cells. Virus-induced lymphopenia worsened cancer-associated lymphocyte loss, and low lymphocyte counts correlated with chronic SARS-CoV-2 RNA shedding, COVID-19 severity and a higher risk of cancer-related death in the first and second surge of the pandemic. Lymphocyte loss correlated with significant changes in metabolites from the polyamine and biliary salt pathways as well as increased blood DNA from Enterobacteriaceae and Micrococcaceae gut family members in long term viral carriers. We surmise that cancer therapies may exacerbate the paradoxical association between lymphopenia and COVID-19-related immunopathology, and that the prevention of COVID-19-induced lymphocyte loss may reduce cancer-associated death.

Published
2021

19. Metabolomic analyses of COVID-19 patients unravel stage-dependent and prognostic biomarkers

Author

Giulia Baciarello, Guido Kroemer, Fanny Pommeret, Allan Sauvat, Eric Solary, Delphine Bredel, Nitharsshini Nirmalathasan, Agathe Dubuisson, Lisa Derosa, Annabelle Stoclin, Frank Griscelli, Mathilde Roumier, Fabrice Andre, Jean-Marie Michot, Frédéric Pène, Claudia Grajeda-Iglesias, Jean-Charles Soria, François-Xavier Danlos, Fabrice Barlesi, Jérôme Duchemin, Flore Rozenberg, Caroline Pradon, Françoise Levavasseur, Anne-Gaëlle Goubet, Julien Rohmer, Luc Mouthon, Laurence Zitvogel, Laurence Albiges, Severine Mouraud, Jean-Eudes Fahrner, Christophe Willekens, Sylvère Durand, Emeline Colomba, Aurélien Marabelle, Félix Ackerman, Syrine Ellouze, Michaela Fontenay, Georges Jourdi, Marc Vasse, Delphine Cantin, 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, 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), 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), Institut Universitaire de France (IUF), Ministère de l'Education nationale, de l’Enseignement supérieur et de la Recherche (M.E.N.E.S.R.), Métabolisme, Cancer et Immunité (CRC - UMR_S 1138), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité)-Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), 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)-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)-Université Paris Cité (UPCité), Service de Médecine Interne [Hôpital Foch, Suresnes] (SMI), Hôpital Foch [Suresnes], Oncologie gynécologique, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Centre de Référence National des Syndromes Hyperéosinophiliques (CEREO), Département de cancérologie de l'enfant et de l'adolescent [Gustave Roussy], Hémostase, Inflammation, Thrombose (HITH - U1176 Inserm - CHU Bicêtre), Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre)-Université Paris-Saclay, Université Paris-Saclay, Département de biologie et pathologie médicales [Gustave Roussy], Département de soins aigus [Gustave Roussy] (DSA), Direction de la recherche [Gustave Roussy], ANR-16-RHUS-0008,LUMIERE,LUMIERE(2016), ANR-18-IDEX-0001,Université de Paris,Université de Paris(2018), and European Project: 825410,ONCOBIOME

Subjects
Male, Cancer Research, Kynurenine pathway, Metabolite, [SDV]Life Sciences [q-bio], Immunology, [SDV.CAN]Life Sciences [q-bio]/Cancer, Disease, Pharmacology, Antibodies, Monoclonal, Humanized, Article, Cellular and Molecular Neuroscience, chemistry.chemical_compound, Metabolomics, Tocilizumab, Intensive care, medicine, Metabolome, Humans, lcsh:QH573-671, Pneumonitis, SARS-CoV-2, business.industry, lcsh:Cytology, COVID-19, Cell Biology, Prognosis, medicine.disease, COVID-19 Drug Treatment, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, chemistry, Viral infection, Female, business, Biomarkers
Abstract

The circulating metabolome provides a snapshot of the physiological state of the organism responding to pathogenic challenges. Here we report alterations in the plasma metabolome reflecting the clinical presentation of COVID-19 patients with mild (ambulatory) diseases, moderate disease (radiologically confirmed pneumonitis, hospitalization and oxygen therapy), and critical disease (in intensive care). This analysis revealed major disease- and stage-associated shifts in the metabolome, meaning that at least 77 metabolites including amino acids, lipids, polyamines and sugars, as well as their derivatives, were altered in critical COVID-19 patient’s plasma as compared to mild COVID-19 patients. Among a uniformly moderate cohort of patients who received tocilizumab, only 10 metabolites were different among individuals with a favorable evolution as compared to those who required transfer into the intensive care unit. The elevation of one single metabolite, anthranilic acid, had a poor prognostic value, correlating with the maintenance of high interleukin-10 and -18 levels. Given that products of the kynurenine pathway including anthranilic acid have immunosuppressive properties, we speculate on the therapeutic utility to inhibit the rate-limiting enzymes of this pathway including indoleamine 2,3-dioxygenase and tryptophan 2,3-dioxygenase.

Published
2021

20. Immune system and intestinal microbiota determine efficacy of androgen deprivation therapy against prostate cancer

Author

Safae Terrisse, Anne-Gaelle Goubet, Kousuke Ueda, Andrew Maltez Thomas, Valentin Quiniou, Cassandra Thelemaque, Garett Dunsmore, Emmanuel Clave, Melissa Gamat-Huber, Satoru Yonekura, Gladys Ferrere, Conrad Rauber, Hang Phuong Pham, Jean-Eudes Fahrner, Eugenie Pizzato, Pierre Ly, Marine Fidelle, Marine Mazzenga, Carolina Alves Costa Silva, Federica Armanini, Federica Pinto, Francesco Asnicar, Romain Daillère, Lisa Derosa, Corentin Richard, Pierre Blanchard, Bertrand Routy, Stéphane Culine, Paule Opolon, Aymeric Silvin, Florent Ginhoux, Antoine Toubert, Nicola Segata, Douglas G McNeel, Karim Fizazi, Guido Kroemer, and Laurence Zitvogel

Subjects
Male, Pharmacology, Cancer Research, Immunology, Prostatic Neoplasms, Androgen Antagonists, adaptive immunity, immunomodulation, Castration-Resistant, Gastrointestinal Microbiome, Prostatic Neoplasms, Castration-Resistant, Mice, prostatic neoplasms, translational medical research, Androgens, Animals, Humans, Immune System, Oncology, Molecular Medicine, Immunology and Allergy
Abstract

BackgroundProstate cancer (PC) responds to androgen deprivation therapy (ADT) usually in a transient fashion, progressing from hormone-sensitive PC (HSPC) to castration-resistant PC (CRPC). We investigated a mouse model of PC as well as specimens from PC patients to unravel an unsuspected contribution of thymus-derived T lymphocytes and the intestinal microbiota in the efficacy of ADT.MethodsPreclinical experiments were performed in PC-bearing mice, immunocompetent or immunodeficient. In parallel, we prospectively included 65 HSPC and CRPC patients (Oncobiotic trial) to analyze their feces and blood specimens.ResultsIn PC-bearing mice, ADT increased thymic cellularity and output. PC implanted in T lymphocyte-depleted or athymic mice responded less efficiently to ADT than in immunocompetent mice. Moreover, depletion of the intestinal microbiota by oral antibiotics reduced the efficacy of ADT. PC reduced the relative abundance of Akkermansia muciniphila in the gut, and this effect was reversed by ADT. Moreover, cohousing of PC-bearing mice with tumor-free mice or oral gavage with Akkermansia improved the efficacy of ADT. This appears to be applicable to PC patients because long-term ADT resulted in an increase of thymic output, as demonstrated by an increase in circulating recent thymic emigrant cells (sjTRECs). Moreover, as compared with HSPC controls, CRPC patients demonstrated a shift in their intestinal microbiota that significantly correlated with sjTRECs. While feces from healthy volunteers restored ADT efficacy, feces from PC patients failed to do so.ConclusionsThese findings suggest the potential clinical utility of reversing intestinal dysbiosis and repairing acquired immune defects in PC patients.

Published
2022

21. 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

22. Trial Watch: Oncolytic viro-immunotherapy of hematologic and solid tumors

Author

Jean-Eudes Fahrner, Jitka Fucikova, John C. Bell, Sarah Levesque, Fabrice Le Boeuf, Radek Spisek, Lorenzo Galluzzi, Derek R. Clements, Jonathan Pol, Shashi Gujar, Samuel T Workenhe, Karen L. Mossman, Laurence Zitvogel, Guido Kroemer, Laetitia Fend, Institut Gustave Roussy (IGR), 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)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Université Sorbonne Paris Cité (USPC), Ligue Nationale Contre le Cancer - Paris, Ligue Nationnale Contre le Cancer, McMaster University [Hamilton, Ontario], Dalhousie University [Halifax], Ottawa Hospital Research Institute [Ottawa] (OHRI), University of Ottawa [Ottawa], University Hospital Motol [Prague], Charles University [Prague] (CU), 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), Service de biologie [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-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)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Karolinska University Hospital [Stockholm], Plateforme de métabolomique, Direction de la recherche [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Weill Medical College of Cornell University [New York], Sandra and Edward Meyer Cancer Center [New-York], Gestionnaire, Hal Sorbonne Université, and Ligue Nationale Contre le Cancer (LNCC)

Subjects
0301 basic medicine, lcsh:Immunologic diseases. Allergy, cavatak, medicine.medical_treatment, Immunology, [SDV.CAN]Life Sciences [q-bio]/Cancer, Review, medicine.disease_cause, lcsh:RC254-282, Food and drug administration, 03 medical and health sciences, maraba mg1, mv-nis, 0302 clinical medicine, Immune system, pexa-vec, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, Immunology and Allergy, In patient, Advanced melanoma, dnx-2401, business.industry, hf10, Immunotherapy, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, 3. Good health, Oncolytic virus, 030104 developmental biology, Herpes simplex virus, Pexa- Vec, Oncology, 030220 oncology & carcinogenesis, t-vec, Cancer cell, Cancer research, reolysin, [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy, business, lcsh:RC581-607
Abstract

International audience; Oncolytic viruses selectively target and kill cancer cells in an immunogenic fashion, thus supporting the establishment of therapeutically relevant tumor-specific immune responses. In 2015, the US Food and Drug Administration (FDA) approved the oncolytic herpes simplex virus T-VEC for use in advanced melanoma patients. Since then, a plethora of trials has been initiated to assess the safety and efficacy of multiple oncolytic viruses in patients affected with various malignancies. Here, we summarize recent preclinical and clinical progress in the field of oncolytic virotherapy.

Published
2018

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