通过CTLA-4阻断进行的抗癌免疫疗法依赖于肠道微生物群。
Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota.
作者信息
Vétizou Marie, Pitt Jonathan M, Daillère Romain, Lepage Patricia, Waldschmitt Nadine, Flament Caroline, Rusakiewicz Sylvie, Routy Bertrand, Roberti Maria P, Duong Connie P M, Poirier-Colame Vichnou, Roux Antoine, Becharef Sonia, Formenti Silvia, Golden Encouse, Cording Sascha, Eberl Gerard, Schlitzer Andreas, Ginhoux Florent, Mani Sridhar, Yamazaki Takahiro, Jacquelot Nicolas, Enot David P, Bérard Marion, Nigou Jérôme, Opolon Paule, Eggermont Alexander, Woerther Paul-Louis, Chachaty Elisabeth, Chaput Nathalie, Robert Caroline, Mateus Christina, Kroemer Guido, Raoult Didier, Boneca Ivo Gomperts, Carbonnel Franck, Chamaillard Mathias, Zitvogel Laurence
机构信息
Institut de Cancérologie Gustave Roussy Cancer Campus (GRCC), 114 rue Edouard Vaillant, 94805 Villejuif, France. INSERM U1015, GRCC, Villejuif, France. University of Paris Sud XI, Kremlin-Bicêtre, France.
Institut National de la Recherche Agronomique (INRA), Micalis-UMR1319, 78360 Jouy-en-Josas, France.
出版信息
Science. 2015 Nov 27;350(6264):1079-84. doi: 10.1126/science.aad1329. Epub 2015 Nov 5.
Antibodies targeting CTLA-4 have been successfully used as cancer immunotherapy. We find that the antitumor effects of CTLA-4 blockade depend on distinct Bacteroides species. In mice and patients, T cell responses specific for B. thetaiotaomicron or B. fragilis were associated with the efficacy of CTLA-4 blockade. Tumors in antibiotic-treated or germ-free mice did not respond to CTLA blockade. This defect was overcome by gavage with B. fragilis, by immunization with B. fragilis polysaccharides, or by adoptive transfer of B. fragilis-specific T cells. Fecal microbial transplantation from humans to mice confirmed that treatment of melanoma patients with antibodies against CTLA-4 favored the outgrowth of B. fragilis with anticancer properties. This study reveals a key role for Bacteroidales in the immunostimulatory effects of CTLA-4 blockade.
靶向细胞毒性T淋巴细胞相关抗原4（CTLA-4）的抗体已成功用作癌症免疫疗法。我们发现，CTLA-4阻断的抗肿瘤作用取决于不同的拟杆菌种类。在小鼠和患者中，针对嗜热栖热菌或脆弱拟杆菌的T细胞反应与CTLA-4阻断的疗效相关。抗生素处理过的或无菌小鼠的肿瘤对CTLA阻断无反应。通过用脆弱拟杆菌灌胃、用脆弱拟杆菌多糖免疫或通过过继转移脆弱拟杆菌特异性T细胞可克服这一缺陷。从人类到小鼠的粪便微生物移植证实，用抗CTLA-4抗体治疗黑色素瘤患者有利于具有抗癌特性的脆弱拟杆菌生长。这项研究揭示了拟杆菌目在CTLA-4阻断的免疫刺激作用中的关键作用。
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