The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide

Sophie Viaud, Fabiana Saccheri, Grégoire Mignot, Takahiro Yamazaki, Romain Daillère, Dalil Hannani, David P. Enot, Christina Pfirschke, Camilla Engblom, Mikael J. Pittet, Andreas Schlitzer, Bernhard Ryffel, Charles O. Elson, Joël Doré, Guido Kroemer, Patricia Lepage, Ivo Gomperts Boneca, François Ghiringhelli, Laurence Zitvogel, Science 342, 971 (2013)

Speaker: Meng-Hsuan Tsai (蔡孟暄)                   Time: 15:00~16:00, Apr. 16, 2014

Commentator: Dr. Li-Jin Hsu (徐麗君 老師)    Place: Room 601

Abstract

Gut microbiota tunes up our immune systems, but its effects on cancer chemotherapy, especially for those treatments that stimulate anticancer immunity, are largely unknown (1). Many cancer patients under chemotherapy develop mucositis and neutropenia, and they usually get antibiotics for preventing infection. However, antibiotic treatment disrupts microbial equilibrium in gut, which may cause unpredicted effects on the chemotherapy. In this study, the authors used animal models to test the link between intestinal microbiota and the efficacy of an anticancer drug, cyclophosphamide (CTX). Their rationale is based on the facts that CTX exerts its therapeutic effect through promoting T_H17 and T_H1 cells, and T_H17 cells are known to be regulated by intestinalmicrobiota (2). The authors found that CTX disrupted the gut barrier and caused intestinal leakage which was accompanied by the translocation of selected species of Gram-positive bacteria into secondary lymphoid organs. Meanwhile, CTX treatment increased the frequency of a special T_H17 cell subset (designated “pathogenic” T_H17, pT_H17) that expressed hallmarks of both T_H1 and T_H17 cells. Notably, germ-free condition or treatment with vancomycin, an antibiotic specific for Gram-positive bacteria, reduced the CTX-driven pT_H17 conversion, which was recovered by reconstitution of some selected Gram-positive bacteria. Furthermore, the antitumor effects of CTX in vivo were significantly impaired under vancomycin treatment, and adoptive transfer of pT_H17 cells partially restored the anticancer efficacy of CTX. These results indicate that gut microbiota is important for cancer chemotherapy through promoting development of anticancer immune cells. Therefore, the potential risks of antibiotic medication during cancer treatments should be taken into consideration.

References

1.     S. I. Grivennikov et al., Adenoma-linked barrier defects and microbial products drive IL-23/IL-17-mediated tumour growth. Nature 491, 254 (Nov 8, 2012).

2.     Ivanov, II et al., Specific microbiota direct the differentiation of IL-17-producing T-helper cells in the mucosa of the small intestine. Cell host & microbe 4, 337 (Oct 16, 2008).