Gut microbiota modulate dendritic cell antigen presentation and radiotherapy-induced antitumor immune response
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
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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Research Article Immunology Oncology

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 4

Vancomycin treatment increases local TAA cross-presentation and antigen recognition in tumors.

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Vancomycin treatment increases local TAA cross-presentation and antigen ...
(A) Ifnb1 mRNA expression levels in TDLNs 1 day after irradiation. (B) Anti-MHC1 (Kb)-SL8 OVA peptide staining on tumor-infiltrating CD11c+ CD103+ DCs 5 days after RT. (C) IFN-γ ELISPOT assay plated with TDLN single-cell suspension and OT1 T cells (1:5 TDLN cells/T cells) in absence (left) or presence (right) of OVA peptide. Cells were harvested 5 days after RT treatment. (D) Coculture of purified CD11c+ DCs from TDLNs from each treatment group were incubated overnight with naive OT1 T cells in an IFN-γ ELISPOT assay (1:10 DCs/T cells). (E) Percentage of IFN-γ expression from overnight OT1 cells cocultured with DCs from mice treated with each therapeutic approach. (F) B16-OVA tumors from mice treated with RT alone or with the RT and vancomycin (RT+VANCO) combination treatment were dissociated and plated with OT1 cells in an IFN-γ ELISPOT plate for 24 hours. n = 5 to 10 mice per group. Data are representative of at least 2 independent experiments. Mean ± SEM are shown. Statistical significance was assessed by Tukey’s test. *P < 0.05, **P < 0.01, ***P < 0.001.