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1. RBD- specific Th1 responses are associated with vaccine-induced protection against SARS-CoV-2 infection in patients with hematological malignancies

Author

Camille Bigenwald, Yacine Haddad, Cassandra Thelemaque, Agathe Carrier, Roxanne Birebent, Pierre Ly, Caroline Flament, Imran Lahmar, Eric de Sousa, Markus Maeurer, Makoto Miyara, Tarek Assi, Cristina Castilla-Llorente, Christophe Willekens, Céline Fayemi, Julien Lazarovici, Aurélien Marabelle, Lisa Derosa, Vincent Ribrag, and Laurence Zitvogel

Subjects
COVID-19, vaccination, T cell, Immunologic diseases. Allergy, RC581-607, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

ABSTRACTThe SARS-CoV-2 pandemic still represents a threat for immunosuppressed and hematological malignancy (HM) bearing patients, causing increased morbidity and mortality. Given the low anti-SARSCoV-2 IgG titers post-vaccination, the COVID-19 threat prompted the prophylactic use of engineered anti-SARS-CoV-2 monoclonal antibodies. In addition, potential clinical significance of T cell responses has been overlooked during the first waves of the pandemic, calling for additional in-depth studies. We reported that the polarity and the repertoire of T cell immune responses govern the susceptibility to SARS-CoV-2 infection in health care workers and solid cancer patients. Here, we longitudinally analyzed humoral and cellular immune responses at each BNT162b2 mRNA vaccine injection in 47 HM patients under therapy. Only one-third of HM, mostly multiple myeloma (MM) bearing patients, could mount S1-RBD-specific IgG responses following BNT162b2 mRNA vaccines. This vaccine elicited a S1-RBD-specific Th1 immune response in about 20% patients, mostly in MM and Hodgkin lymphoma, while exacerbating Th2 responses in the 10% cases that presented this recognition pattern at baseline (mostly rituximab-treated patients). Performing a third booster barely improved the percentage of patients developing an S1-RBD-specific Th1 immunity and failed to seroconvert additional HM patients. Finally, 16 patients were infected with SARS-CoV-2, of whom 6 developed a severe infection. Only S1-RBD-specific Th1 responses were associated with protection against SARS-CoV2 infection, while Th2 responses or anti-S1-RBD IgG titers failed to correlate with protection. These findings herald the paramount relevance of vaccine-induced Th1 immune responses in hematological malignancies.

Published
2023
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2. 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. Synergistic effects of PRIMA-1Met (APR-246) and 5-azacitidine in TP53-mutated myelodysplastic syndromes and acute myeloid leukemia

Author

Nabih Maslah, Norman Salomao, Louis Drevon, Emmanuelle Verger, Nicolas Partouche, Pierre Ly, Philippe Aubin, Nadia Naoui, Marie-Helene Schlageter, Cecile Bally, Elsa Miekoutima, Ramy Rahmé, Jacqueline Lehmann-Che, Lionel Ades, Pierre Fenaux, Bruno Cassinat, and Stephane Giraudier

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

Myelodysplastic syndromes and acute myeloid leukemia with TP53 mutations are characterized by frequent relapses, poor or short responses, and poor survival with the currently available therapies including chemotherapy and 5-azacitidine (AZA). PRIMA-1Met(APR-246,APR) is a methylated derivative of PRIMA-1, which induces apoptosis in human tumor cells through restoration of the transcriptional transactivation function of mutant p53. Here we show that low doses of APR on its own or in combination with AZA reactivate the p53 pathway and induce an apoptosis program. Functionally, we demonstrate that APR exerts these activities on its own and that it synergizes with AZA in TP53-mutated myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML) cell lines and in TP53-mutated primary cells from MDS/AML patients. Low doses of APR on its own or in combination with AZA also show significant efficacy in vivo. Lastly, using transcriptomic analysis, we found that the APR + AZA synergy was mediated by downregulation of the FLT3 pathway in drug-treated cells. Activation of the FLT3 pathway by FLT3 ligand reversed the inhibition of cell proliferation by APR + AZA. These data suggest that TP53-mutated MDS/AML may be better targeted by the addition of APR-246 to conventional treatments.

Published
2020
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5. Combination treatments with hydroxychloroquine and azithromycin are compatible with the therapeutic induction of anticancer immune responses

Author

Peng Liu, Liwei Zhao, Gladys Ferrere, Carolina Alves-Costa-Silva, Pierre Ly, Qi Wu, Ai-Ling Tian, Lisa Derosa, Laurence Zitvogel, Oliver Kepp, and Guido Kroemer

Subjects
covid-19, sars-cov-2, immune checkpoint, hydroxychloroquine, immunotherapy, cancer, Immunologic diseases. Allergy, RC581-607, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Amid controversial reports that COVID-19 can be treated with a combination of the antimalarial drug hydroxychloroquine (HCQ) and the antibiotic azithromycin (AZI), a clinical trial (ONCOCOVID, NCT04341207) was launched at Gustave Roussy Cancer Campus to investigate the utility of this combination therapy in cancer patients. In this preclinical study, we investigated whether the combination of HCQ+AZI would be compatible with the therapeutic induction of anticancer immune responses. For this, we used doses of HCQ and AZI that affect whole-body physiology (as indicated by a partial blockade in cardiac and hepatic autophagic flux for HCQ and a reduction in body weight for AZI), showing that their combined administration did not interfere with tumor growth control induced by the immunogenic cell death inducer oxaliplatin. Moreover, the HCQ+AZI combination did not affect the capacity of a curative regimen (cisplatin + crizotinib + PD-1 blockade) to eradicate established orthotopic lung cancers in mice. In conclusion, it appears that HCQ+AZI does not interfere with the therapeutic induction of therapeutic anticancer immune responses.

Published
2020
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6. Elucidating the gut microbiota composition and the bioactivity of immunostimulatory commensals for the optimization of immune checkpoint inhibitors

Author

Romain Daillère, Bertrand Routy, Anne-Gaëlle Goubet, Alexandria Cogdill, Gladys Ferrere, Carolina Alves-Costa Silva, Aurélie Fluckiger, Pierre Ly, Yacine Haddad, Eugenie Pizzato, Cassandra Thelemaque, Marine Fidelle, Marine Mazzenga, Maria Paula Roberti, Cléa Melenotte, Peng Liu, Safae Terrisse, Oliver Kepp, Guido Kroemer, Laurence Zitvogel, and Lisa Derosa

Subjects
anticancer therapeutics, gut microbiota, cancer, Immunologic diseases. Allergy, RC581-607, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Accumulating evidence from preclinical studies and human trials demonstrated the crucial role of the gut microbiota in determining the effectiveness of anticancer therapeutics such as immunogenic chemotherapy or immune checkpoint blockade. In summary, it appears that a diverse intestinal microbiota supports therapeutic anticancer responses, while a dysbiotic microbiota composition that lacks immunostimulatory bacteria or contains overabundant immunosuppressive species causes treatment failure. In this review, we explore preclinical and translational studies highlighting how eubiotic and dysbiotic microbiota composition can affect progression-free survival in cancer patients.

Published
2020
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7. 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

8. 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

9. Supplementary Figure from Escherichia coli–Specific CXCL13-Producing TFH Are Associated with Clinical Efficacy of Neoadjuvant PD-1 Blockade against Muscle-Invasive Bladder Cancer

Author

Yohann Loriot, Laurence Zitvogel, Jean-Yves Scoazec, Guido Kroemer, Miriam Merad, Fabrice Andre, Benjamin Besse, Michiel S. Van Der Heijden, Nick Van Dijk, Jeroen Van Dorp, Aurélien Marabelle, Lisa Derosa, Gwénaël Le Teuff, Florent Ginhoux, Mathieu Rouanne, Jacques Fieschi, Yves Allory, Camelia Radulescu, Etienne Rouleau, Romain Daillere, Adeline Mallet, Maryse Moya-Nilges, Nadège Cayet, Ivo Gomperts Boneca, Shaima Belhechmi, Baptiste Archambaud, Thibault Raoult, Aymeric Silvin, Kevin Mulder, Garett Dunsmore, François-Xavier Danlos, Camille Bleriot, Jacques Bou Khalil, Gabriel Haddad, Caroline Davin, Mounia Filahi, Thomas Sbarrato, Allan Sauvat, Nicolas Signolle, Virginie Marty, Pierre Ly, Caroline Flament, Marine Mazzenga, Agathe Dubuisson, Idir Ouzaid, Evanguelos Xylinas, Morgan Roupret, Luca Campedel, Carole Helissey, Gwenaelle Gravis, Géraldine Pignot, François Audenet, Constance Thibault, Cédric Lebacle, Cassandra Thelemaque, Maxime Descartes Mbogning-Fonkou, Marianne Gazzano, Isabelle Peguillet, Carolina Alves Costa Silva, Leonardo Lordello, and Anne-Gaëlle Goubet

Abstract

Supplementary Figure from Escherichia coli–Specific CXCL13-Producing TFH Are Associated with Clinical Efficacy of Neoadjuvant PD-1 Blockade against Muscle-Invasive Bladder Cancer

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. Data from Escherichia coli–Specific CXCL13-Producing TFH Are Associated with Clinical Efficacy of Neoadjuvant PD-1 Blockade against Muscle-Invasive Bladder Cancer

Author

Yohann Loriot, Laurence Zitvogel, Jean-Yves Scoazec, Guido Kroemer, Miriam Merad, Fabrice Andre, Benjamin Besse, Michiel S. Van Der Heijden, Nick Van Dijk, Jeroen Van Dorp, Aurélien Marabelle, Lisa Derosa, Gwénaël Le Teuff, Florent Ginhoux, Mathieu Rouanne, Jacques Fieschi, Yves Allory, Camelia Radulescu, Etienne Rouleau, Romain Daillere, Adeline Mallet, Maryse Moya-Nilges, Nadège Cayet, Ivo Gomperts Boneca, Shaima Belhechmi, Baptiste Archambaud, Thibault Raoult, Aymeric Silvin, Kevin Mulder, Garett Dunsmore, François-Xavier Danlos, Camille Bleriot, Jacques Bou Khalil, Gabriel Haddad, Caroline Davin, Mounia Filahi, Thomas Sbarrato, Allan Sauvat, Nicolas Signolle, Virginie Marty, Pierre Ly, Caroline Flament, Marine Mazzenga, Agathe Dubuisson, Idir Ouzaid, Evanguelos Xylinas, Morgan Roupret, Luca Campedel, Carole Helissey, Gwenaelle Gravis, Géraldine Pignot, François Audenet, Constance Thibault, Cédric Lebacle, Cassandra Thelemaque, Maxime Descartes Mbogning-Fonkou, Marianne Gazzano, Isabelle Peguillet, Carolina Alves Costa Silva, Leonardo Lordello, and Anne-Gaëlle Goubet

Abstract

Biomarkers guiding the neoadjuvant use of immune-checkpoint blockers (ICB) are needed for patients with localized muscle-invasive bladder cancers (MIBC). Profiling tumor and blood samples, we found that follicular helper CD4+ T cells (TFH) are among the best therapeutic targets of pembrolizumab correlating with progression-free survival. TFH were associated with tumoral CD8 and PD-L1 expression at baseline and the induction of tertiary lymphoid structures after pembrolizumab. Blood central memory TFH accumulated in tumors where they produce CXCL13, a chemokine found in the plasma of responders only. IgG4+CD38+ TFH residing in bladder tissues correlated with clinical benefit. Finally, TFH and IgG directed against urothelium-invasive Escherichia coli dictated clinical responses to pembrolizumab in three independent cohorts. The links between tumor infection and success of ICB immunomodulation should be prospectively assessed at a larger scale.Significance:In patients with bladder cancer treated with neoadjuvant pembrolizumab, E. coli–specific CXCL13 producing TFH and IgG constitute biomarkers that predict clinical benefit. Beyond its role as a biomarker, such immune responses against E. coli might be harnessed for future therapeutic strategies.This article is highlighted in the In This Issue feature, p. 2221

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. 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

15. Escherichia coli-Specific CXCL13-Producing TFH Are Associated with Clinical Efficacy of Neoadjuvant PD-1 Blockade against Muscle-Invasive Bladder Cancer

Author

Anne-Gaëlle Goubet, Leonardo Lordello, Carolina Alves Costa Silva, Isabelle Peguillet, Marianne Gazzano, Maxime Descartes Mbogning-Fonkou, Cassandra Thelemaque, Cédric Lebacle, Constance Thibault, François Audenet, Géraldine Pignot, Gwenaelle Gravis, Carole Helissey, Luca Campedel, Morgan Roupret, Evanguelos Xylinas, Idir Ouzaid, Agathe Dubuisson, Marine Mazzenga, Caroline Flament, Pierre Ly, Virginie Marty, Nicolas Signolle, Allan Sauvat, Thomas Sbarrato, Mounia Filahi, Caroline Davin, Gabriel Haddad, Jacques Bou Khalil, Camille Bleriot, François-Xavier Danlos, Garett Dunsmore, Kevin Mulder, Aymeric Silvin, Thibault Raoult, Baptiste Archambaud, Shaima Belhechmi, Ivo Gomperts Boneca, Nadège Cayet, Maryse Moya-Nilges, Adeline Mallet, Romain Daillere, Etienne Rouleau, Camelia Radulescu, Yves Allory, Jacques Fieschi, Mathieu Rouanne, Florent Ginhoux, Gwénaël Le Teuff, Lisa Derosa, Aurélien Marabelle, Jeroen Van Dorp, Nick Van Dijk, Michiel S. Van Der Heijden, Benjamin Besse, Fabrice Andre, Miriam Merad, Guido Kroemer, Jean-Yves Scoazec, Laurence Zitvogel, Yohann Loriot, Université Paris-Saclay, 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, NF-kappaB, Différenciation et Cancer (OncokappaB (URP_7324)), Université Paris Cité (UPCité), Immunologie intégrative des tumeurs et immunothérapie des cancers (INTIM), Institut Curie [Paris], Centre d'Immunologie et des Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Petites Molécules de neuroprotection, neurorégénération et remyélinisation, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hôpital d'Instruction des Armées Begin, Service de Santé des Armées, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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), 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), Département d’Innovation Thérapeutique et essais précoces [Gustave Roussy] (DITEP), Direction de la recherche clinique [Gustave Roussy], Service de biostatistique et d'épidémiologie (SBE), Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Département de médecine oncologique [Gustave Roussy], Département de biologie et pathologie médicales [Gustave Roussy], Oncologie gynécologique, ANR-16-RHUS-0008, ANR-21-RHUS-0017, Bristol-Myers Squibb, BMS, Pfizer, Astellas Pharma US, APUS, AstraZeneca, Genentech, Merck, Roche, Gilead Sciences, Meso Scale Diagnostics, MSD, Janssen Pharmaceuticals, Merck Sharp and Dohme, MSD, Horizon 2020 Framework Programme, H2020: 19-CE15-0029-01, 825410, Clovis Oncology, Seerave Foundation, Fondation Philanthropia, Advanced Accelerator Applications, AAA, Agence Nationale de la Recherche, ANR: ANR-10-LABX-62-IBEID, Fondation pour la Recherche Médicale, FRM, Daiichi-Sankyo, Fondation ARC pour la Recherche sur le Cancer, ARC, Ligue Contre le Cancer, Institut Universitaire de France, IUF, Institut National Du Cancer, INCa, Cancéropôle Ile de France, Association Française d'Urologie, AFU, Labex Immuno-Oncology, The trial was conducted by the French Genitourinary Group (GETUG) and funded by MSD, which provided the drug. This study was approved by the ethics committee CPP Est-III in December 2017 and the French National Agency for the Safety of Medicines and Health Products (ANSM) in November 2017, and was conducted in accordance with the protocols and Good Clinical Practice Guidelines defined by the International Conference for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use and the principles of the Declaration of Helsinki., C. Alves Costa Silva reports grants from MSD Avenir Foundation during the conduct of the study. C. Thibault reports personal fees and nonfinancial support from Pfizer, Merck, MSD, Janssen, and Ipsen, grants, personal fees, and nonfinancial support from AstraZeneca, We thank pathologists, nurses, and clinical research associates from Hôpital Européenn George Pompidou, Hôpital Begin, Institut Paoli-Calmettes, Hôpital Bichat, and Hôpital Pitié-Salpétrière for their participation in the PANDORE clinical trial. We are thankful to the flow and mass cytometry facility team of Gustave Roussy (Philippe Rameau and Cyril Catelain). We thank Fluidigm for their support. We are grateful for support for equipment from the French Government Programme Investissements d’Avenir France BioImag-ing (FBI, No. ANR-10-INSB-04-01) and the French Government (Agence Nationale de la Recherche) Investissement d’Avenir program, Laboratoire d’Excellence 'Integrative Biology of Emerging Infectious Diseases' (ANR-10-LABX-62-IBEID). A.-G. Goubet was supported by Fondation pour la Recherche Médicale. C. Alves Costa Silva was supported by MSD Avenir. F.-X. Danlos was supported by Fondation Philantropia. M. Roupret was supported by Fondation Foch and the Association Française d’Urologie (AFU). L. Zitvogel was funded by the RHU Torino Lumière (ANR-16-RHUS-0008). L. Zitvogel and L. Derosa were supported by RHU5 'ANR-21-RHUS-0017' IMMUNOLIFE, SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE), as well as the SIGN’IT ARC foundation. L. Zitvogel was supported by European Union’s Horizon 2020 research and innovation programme under grant agreement number 825410 [project acronym: ONCOBIOME, project title: Gut OncoMicrobiome Signatures (GOMS) associated with cancer incidence, prognosis, and prediction of treatment response]. L. Zitvogel also received an ANR grant–French-German Ileobiome 19-CE15-0029-01. L. Zitvogel and G. Kroemer received a donation from the Seerave Foundation. L. Zitvogel and G. Kroemer were supported by the Ligue contre le Cancer (équipe labelisée), ANR projets blancs, Cancéropôle Ile-de-France, Fondation pour la Recherche Médicale (FRM), a donation by Elior, Institut National du Cancer (INCa), Inserm (HTE), Institut Universitaire de France, the LabEx Immuno-Oncology, and FHU CARE, Dassault, and Badinter Philantropia. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact., Bristol Myers Squibb, and Sanofi, and personal fees from Astellas and AAA during the conduct of the study, as well as personal fees and nonfinancial support from Pfizer, Merck, MSD, Janssen, and Ipsen, grants, personal fees, and nonfinancial support from AstraZeneca, Bristol Myers Squibb, and Sanofi, and personal fees from Astellas and AAA outside the submitted work. F. Audenet reports personal fees from Astellas, Urodiag, Vitadx, and Bristol Myers Squibb, and nonfinancial support from Ipsen outside the submitted work. G. Gravis reports grants from Bristol Myers Squibb, and other support from MSD, Bristol Myers Squibb, and Merck–Pfizer alliance outside the submitted work. C. Helissey reports personal fees from Janssen-Cilag, Roche, Bayer, AstraZeneca, and Astellas outside the submitted work. L. Cam-pedel reports personal fees from MSD, Pfizer, Bristol Myers Squibb, and Bayer outside the submitted work. T. Sbarrato reports personal fees from Veracyte during the conduct of the study. T. Raoult reports grants, personal fees, and nonfinancial support from Merck Sharp & Dohme during the conduct of the study. E. Rouleau reports grants from AstraZeneca, Roche, Clovis, Bristol Myers Squibb, and MSD outside the submitted work. Y. Allory reports other support from Astra-Zeneca, MSD, and Bristol Myers Squibb outside the submitted work. J. Fieschi reports personal fees from Veracyte during the conduct of the study. A. Marabelle reports grants, personal fees, nonfinancial support, and other support from MSD, Bristol Myers Squibb, and AstraZeneca, and personal fees, nonfinancial support, and other support from Roche/Genentech and Pfizer outside the submitted work. J. Van Dorp reports other support from Bristol Myers Squibb during the conduct of the study. M.S. van der Heijden reports grants from Bristol Myers Squibb during the conduct of the study, as well as grants and personal fees from Bristol Myers Squibb, Roche, and AstraZeneca, grants from 4SC, and personal fees from MSD/Merck, Janssen, Pfizer, and Seagen outside the submitted work. B. Besse reports grants from 4D Pharma, AbbVie, Amgen, Aptitude Health, AstraZeneca, BeiGene, Blueprint Medicines, Boehringer Ingelheim, Celgene, Cergentis, Chu-gai Pharmaceutical, Cristal Therapeutics, Daiichi Sankyo, Eli Lilly, Eisai, Genzyme Corporation, GSK, Inivata, Ipsen, Janssen, Onxeo, OSE Immunotherapeutics, Pfizer, Roche/Genentech, Sanofi, Takeda, Tolero Pharmaceuticals, and Turning Point Therapeutics during the conduct of the study. F. Andre reports grants and other support from AstraZeneca and Daiichi Sankyo, grants from Lilly and Sanofi, and other support from Novartis and Relay outside the submitted work. M. Merad reports grants and personal fees from Regeneron, personal fees from Compugen, Morphic Therapeutics, Myeloid Therapeutics, Nirogy, DrenBio, Oncoresponse, Asherbio, Pionyr, Owkin, and Larkspur, other support from Innate Pharma, Genenta, DBV, and OSE Immunotherapeutics, and grants from Boehringer outside the submitted work. G. Kroemer reports grants from Daiichi Sankyo, Eleor, Kaleido, Lytix Pharma, PharmaMar, Osasuna Therapeutics, Samsara Therapeutics, Sanofi, Sotio, Tollys, Vascage, and Vasculox/Tioma, and personal fees from Reithera outside the submitted work, is on the Board of Directors for Bristol Myers Squibb Foundation France, and is a scientific cofounder of EverImmune, Osasuna Therapeutics, Samsara Therapeutics, and Therafast Bio. L. Zitvogel reports grants and personal fees from EverImmune, and grants from 9 Meters and Pileje during the conduct of the study, grants from Daiichi Sankyo outside the submitted work, and a patent for B220028EPA pending. Y. Loriot reports grants from MSD and personal fees from MSD during the conduct of the study, personal fees from Bristol Myers Squibb, Pfizer, Merck Serono, AstraZeneca, Seattle Genetics, Gilead, Taiho, and Astel-las, grants and personal fees from Janssen, and grants from Roche and Celsius outside the submitted work, and a patent for EP2305181.4 pending. No disclosures were reported by the other authors., and FHU CARE, Dassault, and Badinter Philantropia., ANR-16-RHUS-0008,LUMIERE,LUMIERE(2016), and ANR-21-RHUS-0017,IMMUNOLIFE,Microbiota-centered interventions to solve antibiotics-induced primary resistance to immune checkpoint inhibitors(2021)

Subjects
[SDV]Life Sciences [q-bio], Muscles, Programmed Cell Death 1 Receptor, T-Lymphocytes, Helper-Inducer, Chemokine CXCL13, B7-H1 Antigen, Neoadjuvant Therapy, Treatment Outcome, Oncology, Urinary Bladder Neoplasms, Immunoglobulin G, Escherichia coli, Humans, Immune Checkpoint Inhibitors
Abstract

Biomarkers guiding the neoadjuvant use of immune-checkpoint blockers (ICB) are needed for patients with localized muscle-invasive bladder cancers (MIBC). Profiling tumor and blood samples, we found that follicular helper CD4+ T cells (TFH) are among the best therapeutic targets of pembrolizumab correlating with progression-free survival. TFH were associated with tumoral CD8 and PD-L1 expression at baseline and the induction of tertiary lymphoid structures after pembrolizumab. Blood central memory TFH accumulated in tumors where they produce CXCL13, a chemokine found in the plasma of responders only. IgG4+CD38+ TFH residing in bladder tissues correlated with clinical benefit. Finally, TFH and IgG directed against urothelium-invasive Escherichia coli dictated clinical responses to pembrolizumab in three independent cohorts. The links between tumor infection and success of ICB immunomodulation should be prospectively assessed at a larger scale. Significance: In patients with bladder cancer treated with neoadjuvant pembrolizumab, E. coli–specific CXCL13 producing TFH and IgG constitute biomarkers that predict clinical benefit. Beyond its role as a biomarker, such immune responses against E. coli might be harnessed for future therapeutic strategies. This article is highlighted in the In This Issue feature, p. 2221

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. Synergistic effects of PRIMA-1Met (APR-246) and 5-azacitidine in TP53-mutated myelodysplastic syndromes and acute myeloid leukemia

Author

Jacqueline Lehmann-Che, Louis Drevon, Philippe Aubin, Elsa Miekoutima, Marie-Hélène Schlageter, Nicolas Partouche, Cecile Bally, Pierre Fenaux, Nabih Maslah, Lionel Adès, Nadia Naoui, Stéphane Giraudier, Ramy Rahmé, Norman Salomao, Bruno Cassinat, Pierre Ly, and Emmanuelle Verger

Subjects
Chemotherapy, animal structures, Myeloid, business.industry, Myelodysplastic syndromes, medicine.medical_treatment, Azacitidine, Myeloid leukemia, Hematology, medicine.disease, Leukemia, medicine.anatomical_structure, Downregulation and upregulation, Apoptosis, hemic and lymphatic diseases, medicine, Cancer research, business, neoplasms, medicine.drug
Abstract

Myelodysplastic syndromes and acute myeloid leukemia with TP53 mutations are characterized by frequent relapses, poor or short responses, and poor survival with the currently available therapies including chemotherapy and 5-azacitidine (AZA). PRIMA-1Met(APR-246,APR) is a methylated derivative of PRIMA-1, which induces apoptosis in human tumor cells through restoration of the transcriptional transactivation function of mutant p53. Here we show that low doses of APR on its own or in combination with AZA reactivate the p53 pathway and induce an apoptosis program. Functionally, we demonstrate that APR exerts these activities on its own and that it synergizes with AZA in TP53-mutated myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML) cell lines and in TP53-mutated primary cells from MDS/AML patients. Low doses of APR on its own or in combination with AZA also show significant efficacy in vivo Lastly, using transcriptomic analysis, we found that the APR + AZA synergy was mediated by downregulation of the FLT3 pathway in drug-treated cells. Activation of the FLT3 pathway by FLT3 ligand reversed the inhibition of cell proliferation by APR + AZA. These data suggest that TP53-mutated MDS/AML may be better targeted by the addition of APR-246 to conventional treatments.

Published
2019

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. An optimisation framework for improving supply chain performance: case study of a bespoke service provider

Author

Adrien Bailly, John Ahmet Erkoyuncu, Pierre-Ly Pinault, David Bodin, Jim Sibson, Elodie Thai Thien Nghia, Maryam Farsi, and Victor Penella

Subjects
Service (business), Demand management, Optimization, System of systems, Supply chain management, Process management, Computer science, Supply chain, DMAIC, Through-life service, Service provider, Industrial and Manufacturing Engineering, Artificial Intelligence, Fleet management, Performance indicator, Bespoke
Abstract

A service supply chain can be described as a system of systems with a highly interactive and complex network of suppliers, service providers, OEMs and customers. Supply chain management could create value for bespoke service providers, customers and stakeholders cooperating through the supply chain. Bespoke service provider companies are responsible for managing their asset based on different service contracts and possibly through the end of the asset lifetime. Providing a through-life service requires tailored strategic dimensions to measure the supply chain performance. The performance can be evaluated with regards to several supply chain elements such as demand management, procurement, logistics, etc. This article takes a different angle to the current supply chain performance frameworks by discussing performance through DMAIC cycle. Considering a through-life service, this paper presents a performance optimization framework to improve the supply chain performance in terms of an asset or component availability and cost of service. Moreover, an exhaustive list of KPIs to evaluate the supply chain performance are identified. A case study of fleet management for a bespoke service provider is considered to test the validity of the framework. The DMAIC technique has demonstrated to be an effective method to improve supply chain strategies and performance. Cranfield University

Published
2020

22. Elucidating the gut microbiota composition and the bioactivity of immunostimulatory commensals for the optimization of immune checkpoint inhibitors

Author

Marine Mazzenga, Carolina Alves Costa Silva, Marine Fidelle, Laurence Zitvogel, Yacine Haddad, Alexandria P. Cogdill, Lisa Derosa, Gladys Ferrere, Maria Paula Roberti, Peng Liu, Cassandra Thelemaque, Anne-Gaëlle Goubet, Pierre Ly, Safae Terrisse, Romain Daillère, Cléa Melenotte, Aurélie Fluckiger, Eugenie Pizzato, Bertrand Routy, Guido Kroemer, Oliver Kepp, 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, Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM), 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, The University of Texas M.D. Anderson Cancer Center [Houston], 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 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.), 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), ANR-16-RHUS-0008,LUMIERE,LUMIERE(2016), European Project: 825410,ONCOBIOME, École pratique des hautes études (EPHE), Sow, Cissé, LUMIERE - - LUMIERE2016 - ANR-16-RHUS-0008 - RHUS - VALID, European Union’s Horizon 2020 research and innovation programme under grant agreement. - ONCOBIOME - 825410 - INCOMING, and ANR-18-IDEX-0001,Université de Paris,Université de Paris(2018)

Subjects
0301 basic medicine, Immune checkpoint inhibitors, [SDV]Life Sciences [q-bio], Immunology, Review, Anticancer therapeutics, Biology, Gut flora, digestive system, Treatment failure, 03 medical and health sciences, 0302 clinical medicine, Neoplasms, medicine, Immunology and Allergy, Humans, Symbiosis, [SDV.MP] Life Sciences [q-bio]/Microbiology and Parasitology, Immune Checkpoint Inhibitors, RC254-282, ComputingMilieux_MISCELLANEOUS, Cancer, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, gut microbiota, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC581-607, medicine.disease, Commensalism, biology.organism_classification, Immune checkpoint, Gastrointestinal Microbiome, [SDV] Life Sciences [q-bio], 030104 developmental biology, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Oncology, 030220 oncology & carcinogenesis, Dysbiosis, Immunologic diseases. Allergy, Microbiota composition, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; Accumulating evidence from preclinical studies and human trials demonstrated the crucial role of the gut microbiota in determining the effectiveness of anticancer therapeutics such as immunogenic chemotherapy or immune checkpoint blockade. In summary, it appears that a diverse intestinal microbiota supports therapeutic anticancer responses, while a dysbiotic microbiota composition that lacks immunostimulatory bacteria or contains overabundant immunosuppressive species causes treatment failure. In this review, we explore preclinical and translational studies highlighting how eubiotic and dysbiotic microbiota composition can affect progression-free survival in cancer patients.

Published
2020
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23. Profil d’effets indésirables des antagonistes R-NMDA : analyse de clusters des signaux de disproportionnalité extraits de Vigibase®

Author

Pierre Ly, Nhan-Taï, Université Grenoble Alpes - UFR Pharmacie (UGA UFRP), Université Grenoble Alpes (UGA), and Bruno Revol

Subjects
Antagonistes des Récepteurs NMDA, Analyse de clusters, Analyse de disproportionnalité, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, Data mining
Abstract

Mémoire de Diplôme d'Etudes Spécialisées (DES) tenant lieu de thèse d'exercice.; NMDA R antagonists are a class of drugs widely used to treat various diseases such as pain. Currently, only four drugs are on the market. However, their side effects, particularly psychodysleptic limit their development. Our cluster analysis identified adverse events that delineate the typical safety profile of an R-NMDA antagonist. This includes expected psychiatric and neurological disorders, such as hallucinations or deliria but also arrhythmias, blood pressure disorders, respiratory failures, micturition, vision, musculoskeletal and gastrointestinal disorders. On the contrary, adverse reactions specific to one or two drugs have been identified. There is a risk of abuse and dependence but also of immuno-allergic effects with ketamine and dextromethorphan. Amantadine and memantine have in common frail elderly-related adverse drugs reactions. Finally, the hepatobiliary and uro-nephrological damage specific to chronic misuse of ketamine, as well as some specific adverse effects of amantadine (livedo reticularis) and dextromethorphan (acute generalised exanthematous pustulosis) have been identified. The innovative approach of this method is based on the hierarchical classification of adverse reactions by an algorithm (data clustering). However, due to the many biases inherent in the methodology used, further investigations are needed.; Les antagonistes des R-NMDA font l’objet de nombreuses études dans la prise en charge de diverses pathologies, telles que la douleur. A l’heure actuelle, seuls quatre médicaments sont commercialisés. Leurs nombreux effets indésirables, notamment de type psychodysleptique, limitent néanmoins leur développement. Notre analyse de clusters a permis d’isoler des effets indésirables qui correspondraient au profil type d’un antagoniste des R-NMDA. Celui-ci comporte ainsi des troubles psychiatriques et neurologiques attendus, tels que des hallucinations ou des délires, mais aussi des arythmies, des troubles de la pression artérielle, des insuffisances respiratoires, des troubles de la miction, de la vision, des troubles musculo-squelettiques et gastro-intestinaux. Au contraire, des effets indésirables propres à un ou deux médicaments ont été identifiés. La kétamine et le dextrométhorphane partagent le risque d’abus et de dépendance, mais aussi des effets immuno-allergiques. L'amantadine et la mémantine ont en commun des effets indésirables liés aux personnes âgées, présentant des comorbidités. Enfin, les risques d’atteintes hépato-bliaire et uro-néphrologique spécifiques du mésusage chronique de la kétamine, ainsi que certains effets indésirables caractéristiques de l'amantadine (livedo reticularis) et du dextrométhorphane (pustulose exanthématique aiguë généralisée) ont été identifiés. L’originalité de la méthode repose sur la classification hiérarchique des effets indésirables par un algorithme (data clustering). Cependant, les nombreux biais inhérents à la méthodologie utilisée nécessitent une confirmation par des études plus robustes.

Published
2019

24. Adventures on the China Wine Trail : How Farmers, Local Governments, Teachers, and Entrepreneurs Are Rocking the Wine World

Author

Cynthia Howson, Pierre Ly, Cynthia Howson, and Pierre Ly

Subjects
Wine industry--China, Wine and wine making--Social aspects--China, Wine tourism--China
Abstract

Could China take over the wine world? Cynthia Howson and Pierre Ly explore how Chinese wine went from being ignored and ridiculed to earning gold medals and praise by famous critics in less than a decade.Wine made in… China? Until recently, for most people, at best, it didn't exist. Or at worst, as one colorful tasting note described, it evoked: “ash tray, coffee grounds, and urinal crust.” Then, a 2009 Chinese red shocked the world when it won Best Bordeaux Blend at the Decanter World Wine Awards. Could China take over the wine world? Cynthia Howson and Pierre Ly provide a knowledgeable and exuberant exploration of how Chinese wine went from being ignored and ridiculed to earning gold medals and praise by famous critics in less than a decade. They take the reader along on their adventure on the China wine trail to meet the farmers, entrepreneurs, and teachers who are shaping this new industry. They travel to Chinese wine tourism hotspots, talk to winemakers who struggle to find good wine grapes, and visit lush mountaintops and arid deserts to see what French multinational corporations have in common with small family farms. Then, they visit a Chinese wine school to meet professors and their students eager to join the wine work force. They reveal where they bought the best local wines as they give travelers new insights on China and ideas for Chinese wine tourism. Readers interested in current affairs, economic development, and business in China will find that wine offers a clear lens for understanding the larger issues facing the country.

Published
2020

25. The charitable activities of terrorist organizations

Author

Pierre Ly

Subjects
Economics and Econometrics, Sociology and Political Science, Social work, business.industry, Order (exchange), Terrorism, Economics, Public policy, Public relations, business, Public finance
Abstract

Violent groups sometimes invest significant resources in social work, notably in the form of charities and NGOs. The present paper models a terrorist group's charities as a means to advertise its cause in order to raise popular support. The analysis explains how different types of organizations arise in equilibrium, depending on government policies. Then, the interaction between a purely terrorist group and an independent local NGO is examined. It is shown that a purely terrorist group always invests in more attacks than an integrated terrorist-charity organization. Furthermore, the latter may have more NGO activity than a separate local NGO.

Published
2006

27. Individual Preferences Over NGO Projects: Evidence from Microlending on Kiva

Author

Pierre Ly and Geri Mason

Subjects
Finance, Microfinance, Actuarial science, Poverty, law, business.industry, Juvenile delinquency, Developing country, business, Popularity, law.invention
Abstract

Peer to peer (P2P) microfinance connects philanthropic citizens with poor entrepreneurs in the developing world. Although its popularity has grown exponentially with the creation of several competing online platforms, very little is known about how individual lenders behave and whether their priorities differ from those of traditional development practitioners. This paper presents evidence on how individual lenders choose between borrowers, and how lenders' preferences relate to the objectives of the microfinance sector. Using data from Kiva.org, we present estimates of the impact of publicly visible project characteristics on funding speed. Results suggest that Kiva lenders rationally consider indicators of the likelihood of repayment as well as borrowers' need. Smaller loans, groups and women get funded faster as do loans to sectors of activity with low entry costs. Meanwhile, loans requested to finance education and health projects or those advertised by NGOs with better risk ratings, and lower default and delinquency rates, fund faster. The results imply that policy makers and practitioners who seek to use microfinance as a poverty alleviation tool should invest in the P2P approach.

Published
2010

28. Competition Between NGO Projects: Evidence from Kiva

Author

Geri Mason and Pierre Ly

Subjects
Competition (economics), Microfinance, Public economics, law, business.industry, media_common.quotation_subject, Economics, Public relations, Empirical evidence, business, Welfare, media_common, law.invention
Abstract

This paper investigates the effect of competition between NGO projects on their ability to raise funds, using the case of Kiva, an online peer-to-peer (P2P) microlending website. Although NGO behavior in competitive environments is often subject to controversy, there is little formal empirical evidence to illustrate theoretical findings and inform policy. We find that competition has a sizable negative impact on projects' funding speed and that the effect is stronger between close substitutes. These results illustrate several key findings in the theoretical literature and suggest that regulating the entry of projects on charitable P2P platforms may sometimes improve welfare. Furthermore, we find that increases in the lender side of the market generated by media exposure improve funding speed and relax the impact of competition. Our findings shed light on the way media exposure affects NGOs' fundraising success.

Published
2010

29. My Money Versus Your Money: An Examination of NGOs' Income and Expenditure; Evidence From UK International NGOs

Author

Pierre Ly

Subjects
Labour economics, Comprehensive income, Total personal income, business.industry, Economics, Gross income, Distribution (economics), Demographic economics, business, Income in kind, Panel data
Abstract

Non Governmental Organizations (NGOs) have various sources of income and expenditure. They have donated and commercial incomes, and they spend them on both charitable and non-charitable expenditure. Standard economic theory implies that different sources of income are fungible, which means that income elasticities should be the same across income and expenditure categories. This paper seeks to test that assumption using panel data on 74 UK-based international NGOs. I find that changes in donated income primarily affect charitable expenditures, while changes in commercial income sources seem to affect mostly expenditures that relate less to the NGO's charitable mission. These findings suggest that income is not fungible but that NGOs have mental accounts.

Published
2006

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