Gut Bacteria Composition Drives Primary Resistance to Cancer Immunotherapy in Renal Cell Carcinoma Patients
2020
Derosa, Lisa | Routy, Bertrand | Fidelle, Marine | Iebba, V.Alerio | Alla, Laurie | Pasolli, Edoardo | Segata, Nicola | Desnoyer, Aude | Pietrantonio, Filippo | Ferrere, Gladys, G. | Fahrner, Jean-Eudes | Le Chatellier, Emmanuelle | Pons, Nicolas | Galleron, Nathalie | Roume, Hugo | Duong, Connie p.M. | Mondragón, Laura | Iribarren, Kristina | Bonvalet, Mélodie | Terrisse, Safae | Rauber, Conrad | Goubet, Anne Gaelle | Daillere, Romain | Lemaitre, Fabien | Reni, Anna | Casu, Beatrice | Tidjani Alou, Maryam | Costa Silva, Caroline Alves | Raoult, Didier | Fizazi, Karim | Escudier, Bernard | Kroemer, Guido, E | Albiges, Laurence | Zitvogel, Laurence | 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) ; Università degli Studi di Trento = University of Trento (UNITN) | 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 Evolution Phylogénie et Infections (MEPHI) ; Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU) | 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
International audience
显示更多 [+] 显示较少 [-]英语. 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 NIVO-REN 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. (c) 2020 Published by Elsevier B.V. on behalf of European Association of Urology.
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