The Intestinal Microbiota Modulates the Anticancer Immune Effects of Cyclophosphamide

We demonstrate that cyclophosphamide alters the composition of microbiota in the small intestine and induces the translocation of selected species of Gram+ bacteria into secondary lymphoid organs

Sophie Viaud; Fabiana Saccheri; Grégoire Mignot; Takahiro Yamazaki; Romain Daillère; Dalil Hannani; David P. Enot; Christina Pfirschke; Camilla Engblom; Mikael J. Pittet; Andreas Schlitzer; Florent Ginhoux; Lionel Apetoh; Elisabeth Chachaty; Paul-Louis Woerther; Gérard Eberl; Marion Bérard; Chantal Ecobichon; Dominique Clermont; Chantal Bizet; Valérie Gaboriau-Routhiau; Nadine Cerf-Bensussan; Paule Opolon; Nadia Yessaad; Eric Vivier; Bernhard Ryffel; Charles O. Elson; Joël Doré; Guido Kroemer; Patricia Lepage; Ivo Gomperts Boneca; François Ghiringhelli; Laurence Zitvogel

2013

Scholarcy highlights

  • Cyclophosphamide is one of several clinically important cancer drugs whose therapeutic efficacy is due in part to their ability to stimulate anti-tumor immune responses
  • Anticancer chemotherapeutics often cause mucositis and neutropenia, two complications that require treatment with antibiotics, which in turn can result in dysbiosis
  • Disruption of the intestinal barrier was accompanied by a significant translocation of commensal bacteria in >50% mice into mesenteric lymph nodes and spleens that was well detectable 48 h post-CTX, less so after doxorubicin treatment
  • The two pattern recognition receptors, nucleotide-binding oligomerization domain-containing1 and Nod2, were dispensable for the CTX-induced raise in splenic pathogenicT helper 17 cells and for the tumor growth retarding effects of CTX. These results establish the capacity of CTX to stimulate pTh17 cells through a complex circuitry that involves intestinal bacteria and myeloid differentiation primary response gene 88, correlating with its anticancer effects
  • We addressed whether Gram+ bacterial species that translocated into secondary lymphoid organs in response to CTX could polarize naïve CD4+ T cells towards a Th1 or Th17 pattern
  • Driven by the observations that CTX mostly induced the translocation of Gram+ bacteria and that Gram+ bacteria correlated with splenic Th1/Th17 polarization, we compared the capacity of several ATB regimens, namely vancomycin and colistin to interfere with the tumor growth-inhibitory effects of CTX
  • To establish a direct causal link between these phenomena, we adoptively transferred Th17 or pathogenicT helper 17 populations into vancomycin-treated mice and evaluated their capacity to reestablish the CTX-mediated tumor growth retardation

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