Gut Bacteria Composition Drives Primary Resistance to Cancer Immunotherapy in Renal Cell Carcinoma Patients.

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.

To evaluate the predictive value of stool bacteria composition for ICB efficacy in a cohort of advanced RCC patients.

We prospectively collected fecal samples from 69 advanced RCC patients treated with nivolumab and enrolled in the GETUG-AFU 26 NIVOREN microbiota translational substudy phase 2 trial (NCT03013335) at Gustave Roussy. We recorded patient characteristics including ATB use, prior systemic therapies, and response criteria. We analyzed 2994 samples of feces from healthy volunteers (HVs). In parallel, preclinical studies performed in RCC-bearing mice that received fecal transplant (FMT) from RCC patients resistant to ICB (NR-FMT) allowed us to draw a cause-effect relationship between gut bacteria composition and clinical outcomes for ICB. The influence of tyrosine kinase inhibitors (TKIs) taken before starting nivolumab on the microbiota composition has also been assessed.

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.

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).

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.

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.

European urology. 2020 May 03 [Epub ahead of print]

Lisa Derosa, Bertrand Routy, Marine Fidelle, Valerio Iebba, Laurie Alla, Edoardo Pasolli, Nicola Segata, Aude Desnoyer, Filippo Pietrantonio, Gladys Ferrere, Jean-Eudes Fahrner, Emmanuelle Le Chatellier, Nicolas Pons, Nathalie Galleron, Hugo Roume, Connie P M Duong, Laura Mondragón, Kristina Iribarren, Mélodie Bonvalet, Safae Terrisse, Conrad Rauber, Anne-Gaëlle Goubet, Romain Daillère, Fabien Lemaitre, Anna Reni, Beatrice Casu, Maryam Tidjani Alou, Carolina Alves Costa Silva, Didier Raoult, Karim Fizazi, Bernard Escudier, Guido Kroemer, Laurence Albiges, Laurence Zitvogel

Gustave Roussy Cancer Campus (GRCC), Villejuif, France; Institut National de la Santé et de la Recherche Médicale (INSERM) U1015, Équipe Labellisée-Ligue Nationale contre le Cancer, Villejuif, France; Faculté de Médecine Kremlin-Bicêtre, Université Paris Sud, Université Paris Saclay, France; Department of Medical Oncology, Gustave Roussy Cancer Campus (GRCC), Villejuif, France. Electronic address: ., Hematology-Oncology Division, Department of Medicine, Centre Hospitalier de l'Université de Montréal (CHUM), Montréal, QC, Canada; Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal l, Canada CHUM, Montréal, QC, Canada., Gustave Roussy Cancer Campus (GRCC), Villejuif, France; Institut National de la Santé et de la Recherche Médicale (INSERM) U1015, Équipe Labellisée-Ligue Nationale contre le Cancer, Villejuif, France; Faculté de Médecine Kremlin-Bicêtre, Université Paris Sud, Université Paris Saclay, France; Center of Clinical Investigations in Biotherapies of Cancer (CICBT) 1428, Villejuif, France; Faculté de Pharmacie, University Paris-Saclay, Chatenay-Malabry, France., Gustave Roussy Cancer Campus (GRCC), Villejuif, France; Institut National de la Santé et de la Recherche Médicale (INSERM) U1015, Équipe Labellisée-Ligue Nationale contre le Cancer, Villejuif, France., Université Paris-Saclay, INRAE MetaGenoPolis, Jouy-en-Josas, France., Department of Agricultural Sciences, University of Naples Federico II, Napoli, Italy., Department CIBIO, University of Trento, Trento, Italy; Istituto Europeo di Oncologie, Milan, Italy., Gustave Roussy Cancer Campus (GRCC), Villejuif, France; Faculté de Pharmacie, University Paris-Saclay, Chatenay-Malabry, France; Gustave Roussy Cancer Campus, Laboratory of Immunomonitoring in Oncology, CNRS-UMS 3655 and INSERM-US23, Villejuif, France., IRCCS Istituto Nazionale dei Tumori Foundation, Milan, Italy., Gustave Roussy Cancer Campus (GRCC), Villejuif, France; Institut National de la Santé et de la Recherche Médicale (INSERM) U1015, Équipe Labellisée-Ligue Nationale contre le Cancer, Villejuif, France; Faculté de Médecine Kremlin-Bicêtre, Université Paris Sud, Université Paris Saclay, France; Transgene S.A., Illkirch-Graffenstaden, France., Faculté de Médecine Kremlin-Bicêtre, Université Paris Sud, Université Paris Saclay, France; Cell Biology and Metabolomics Platforms, Gustave Roussy Cancer Campus, Villejuif, France; Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, INSERM U1138, Centre de Recherche des Cordeliers, Paris, France., EverImmune, GRCC, Villejuif, France., Gustave Roussy Cancer Campus (GRCC), Villejuif, France; Institut National de la Santé et de la Recherche Médicale (INSERM) U1015, Équipe Labellisée-Ligue Nationale contre le Cancer, Villejuif, France; Faculté de Médecine Kremlin-Bicêtre, Université Paris Sud, Université Paris Saclay, France; Department of Medical Oncology, Gustave Roussy Cancer Campus (GRCC), Villejuif, France., Gustave Roussy Cancer Campus (GRCC), Villejuif, France; Institut National de la Santé et de la Recherche Médicale (INSERM) U1015, Équipe Labellisée-Ligue Nationale contre le Cancer, Villejuif, France; Faculté de Médecine Kremlin-Bicêtre, Université Paris Sud, Université Paris Saclay, France., Aix-Marseille Université, MEPHI, IRD, IHU Méditerranée Infection, Marseille, France., Gustave Roussy Cancer Campus (GRCC), Villejuif, France; Department of Medical Oncology, Gustave Roussy Cancer Campus (GRCC), Villejuif, France., Cell Biology and Metabolomics Platforms, Gustave Roussy Cancer Campus, Villejuif, France; Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, INSERM U1138, Centre de Recherche des Cordeliers, Paris, France; EverImmune, GRCC, Villejuif, France; Aix-Marseille Université, MEPHI, IRD, IHU Méditerranée Infection, Marseille, France; Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France; Suzhou Institute for Systems Medicine, Chinese Academy of Medical Sciences, Suzhou, China; Department of Women's and Children's Health, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden., Gustave Roussy Cancer Campus (GRCC), Villejuif, France; Faculté de Médecine Kremlin-Bicêtre, Université Paris Sud, Université Paris Saclay, France; Department of Medical Oncology, Gustave Roussy Cancer Campus (GRCC), Villejuif, France., Gustave Roussy Cancer Campus (GRCC), Villejuif, France; Institut National de la Santé et de la Recherche Médicale (INSERM) U1015, Équipe Labellisée-Ligue Nationale contre le Cancer, Villejuif, France; Faculté de Médecine Kremlin-Bicêtre, Université Paris Sud, Université Paris Saclay, France; Department of Medical Oncology, Gustave Roussy Cancer Campus (GRCC), Villejuif, France; Center of Clinical Investigations in Biotherapies of Cancer (CICBT) 1428, Villejuif, France; EverImmune, GRCC, Villejuif, France; Suzhou Institute for Systems Medicine, Chinese Academy of Medical Sciences, Suzhou, China. Electronic address: .

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