Skip to search
Skip to main content
Back to Search
Start Over
Escherichia coli-Specific CXCL13-Producing TFH Are Associated with Clinical Efficacy of Neoadjuvant PD-1 Blockade against Muscle-Invasive Bladder Cancer
Authors :
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) ANR-21-RHUS-0017,IMMUNOLIFE,Microbiota-centered interventions to solve antibiotics-induced primary resistance to immune checkpoint inhibitors(2021)
Source :
Cancer Discovery, Cancer Discovery, 2022, 12 (10), pp.2280-2307. ⟨10.1158/2159-8290.CD-22-0201⟩
Publication Year :
2022
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
Details
ISSN :
21598290
Volume :
12
Issue :
10
Database :
OpenAIRE
Journal :
Cancer discovery
Accession number :
edsair.doi.dedup.....dbf819f562fb400a994987a64778ef6e