Gut microbiota modulate dendritic cell antigen presentation and radiotherapy-induced antitumor immune response
Mireia Uribe-Herranz, … , Constantinos Koumenis, Andrea Facciabene
Mireia Uribe-Herranz, … , Constantinos Koumenis, Andrea Facciabene
Published December 9, 2019
Citation Information: J Clin Invest. 2020;130(1):466-479. https://doi.org/10.1172/JCI124332.
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Gut microbiota modulate dendritic cell antigen presentation and radiotherapy-induced antitumor immune response

Abstract

Alterations in gut microbiota impact the pathophysiology of several diseases, including cancer. Radiotherapy (RT), an established curative and palliative cancer treatment, exerts potent immune modulatory effects, inducing tumor-associated antigen (TAA) cross-priming with antitumor CD8+ T cell elicitation and abscopal effects. We tested whether the gut microbiota modulates antitumor immune response following RT distal to the gut. Vancomycin, an antibiotic that acts mainly on gram-positive bacteria and is restricted to the gut, potentiated the RT-induced antitumor immune response and tumor growth inhibition. This synergy was dependent on TAA cross presentation to cytolytic CD8+ T cells and on IFN-γ. Notably, butyrate, a metabolite produced by the vancomycin-depleted gut bacteria, abrogated the vancomycin effect. In conclusion, depletion of vancomycin-sensitive bacteria enhances the antitumor activity of RT, which has important clinical ramifications.

Authors

Mireia Uribe-Herranz, Stavros Rafail, Silvia Beghi, Luis Gil-de-Gómez, Ioannis Verginadis, Kyle Bittinger, Sergey Pustylnikov, Stefano Pierini, Renzo Perales-Linares, Ian A. Blair, Clementina A. Mesaros, Nathaniel W. Snyder, Frederic Bushman, Constantinos Koumenis, Andrea Facciabene

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Figure 2

The effects of vancomycin are abrogated in CD8-depleted mice.

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The effects of vancomycin are abrogated in CD8-depleted mice. (A) Quanti...
(A) Quantification of CD3+ cell infiltration by immunohistochemistry of B16-OVA–derived primary tumor sections from untreated, vancomycin treatment alone (Vanco), RT treatment alone (RT), or vancomycin plus RT combination treatment (RT+Vanco), and of abscopal tumor sections from RT abscopal or RT+Vanco abscopal combination treated. Mean ± SEM are shown. Statistical significance was assessed by Tukey’s test. (B) Primary tumors from each treatment group were digested and individual cells were analyzed by flow cytometry to determine the percentage of OVA-specific CD8+ T cells (CD45+/CD3+/CD8+/TET-OVA). Mean ± SEM are shown. Statistical significance was assessed by Tukey’s test. (C) Tumor growth rates in CD8-depleted mice. n = 5 to 10 mice per group. Mean ± SEM are shown. Statistical significance was assessed by 2-way ANOVA. Data are representative of at least 2 independent experiments. *P < 0.05, **P < 0.001, ***P < 0.01.