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The Intestinal Microbiota Modulates the Anticancer Immune
Effects of Cyclophosphamide
by 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, PaulLouis 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, and
Laurence Zitvogel
Science
Volume 342(6161):971-976
November 22, 2013
Published by AAAS
• Cyclophosphamide (CTX) is a clinically important cancer drug whose
therapeutic efficacy is in part due to stimulate antitumor immune response.
• In mice, they demonstrate that cyclophosphamide alters the composition
of small intestine microbiota and induces the translocation of selected
species of Gram+ bacteria into secondary lymphoid organs.
• There, these bacteria stimulate the generation of “pathogenic” T helper 17
cells (pTh17) and memory Th1 immune responses.
• Tumor-bearing mice either germ free or Gram+ bacteria depleted showed
a reduction in pTh17 responses and their tumors were resistant to
cyclophosphamide.
• Adoptive transfer of pTh17 cells in these mice partially restored the
antitumor efficacy of cyclophosphamide.
The gut microbiota help shape the anticancer immune response.
How do they demonstrate this?
Characterization of the inflammatory status of the gut epithelial barrier 48 hours
after therapy with CTX or anthracycline doxorubicin in naive mice.
Goblet cells in villi
Paneth cells in crypts
Immunofluorescence micrographs
Orally administered fluorescein
isothiocyanate became detectable in
the blood 18 hours after CTX
treatment confirming an increase in
intestinal permeability.
Disruption of the intestinal barrier was accompanied by a significant translocation of
commensal bacteria in >50% mice into mesenteric lymph nodes and spleens
detectable 48 hours after CTX treatment.
• QPCR was applied to determine
the relative abundance,
compared to all bacteria, of
targeted groups of bacteria in the
small intestine mucosa from CTXtreated/control, naive and tumor
bearing mice.
• In tumor bearers the total
amount of bacteria 7 days after
CTX treatment, as well as
Clostridium leptum group, was
not affected.
• However there is a reduction in
the abundance of lactobacilli and
enterococci, revealing the
capacity of CTX to provoke the
selective translocation of some
Gram positive species.
• From previous works they know that CTX induces the polarization of splenic CD4 T
cells toward a Th1 and Th17 pattern.
• The gut microbiota is indispensable for driving the conversion of naive CD4 T cells
into IL-17 producers is response to CTX.
• Sterilization of the gut by broad spectrum antibiotics or treatment of mice with
vancomycin, reduces the CTX induced Th17 conversion.
IL-17
• In conventional SPF mice, the counts of lactobacilli and SFB measured in small
intestine mucosa positively correlated with the Th1 and Th17 polarization of
splenocytes. Not for Clostridium.
• These results point to a specific association between particular microbial components
present in the gut lumen and the polarity of TH responses induced by CTX treatment.
CTX increases the frequency of “pathogenic” TH17 cells which share hallmarks of TH1
and TH17 cells within the spleen. This response is dependent on the gut microbiota.
• They addressed whether Gram-positive
bacterial species that translocated into
secondary lymphoid organs in response to
CTX could polarize naive CD4 T cells toward a
TH1 and TH17 pattern.
• Orally fed L. johnsonii and E. hirae facilitate
the reconstitution of the pool of pTH17 cells
in the spleen of ATB-treated SPF mice.
• They postulate that the translocation of a
specific set of Gram-positive commensal
bacteria is necessary and sufficient to
mediated the CTX-driven accumulation of
pTH17 cells and TH1 bacteria-specific memory
T cell responses.
Effect of antibiotics on CTX-mediated
tumor growth inhibition (P815
mastocytomas).
• They monitored the effects of CTX
against MCA205 sarcomas in different
conditions.
• They saw that in germ-free mice or
treated with Vancomycin/Colistin, CTX
works not so well in reducing the tumor
size with respect to the control (SPF).
• What they saw: specific CTX-induced alterations in gut microbiota-accumulation of
pTH17 cells in the spleen-success of chemotherapy.
•To establish a direct causal link between these phenomena they transferred TH17 or
pTH17 populations into vancomycin-treated mice and evaluated their capacity to
restablish the CTX-mediated tumor growth retardation.
• Only pTH17, but not TH17 cells, could rescue the negative impact of Vancomycin on the
CTX-mediated therapeutic effect.
•The present study unveils the impact of gut
microbiota on chemoterapy-elicited anticancer
immune responses.
• New risks associated with antibiotic medication
during cancer treatments
• Potential therapeutic utiliy of manipulating the gut
microbiota
Thank you!!