Vancomycin Treatment Increases Efficacy of Radiotherapy in Mice

Variations in the gut microbiota are increasingly being found to influence diseases and may also mediate responses to drugs and other therapies. Using mouse models of melanoma and lung and cervical cancers, Uribe-Herranz, Rafail, Beghi, Gil-de-Gómez, and colleagues found a previously unknown role for gut microbes in the response to radiotherapy. Specifically, oral administration of vancomycin, an antibiotic that predominantly targets gram-positive bacteria, selected because it is not known to have any systemic effects, improved both the direct and abscopal antitumor effects of radiotherapy. Treatment with vancomycin increased the population of cytolytic CD8⁺ T cells within tumors following radiotherapy, and the beneficial effects of the drug were lost in CD8⁺ T cell–depleted mice. Ifng (encoding IFNγ) mRNA and IFNγ protein levels were increased in mice treated with both vancomycin and radiotherapy, and experiments in Ifng-knockout mice confirmed that the antitumor effects of combination vancomycin treatment and radiotherapy were dependent on IFNγ. The increased antitumor activity of CD8⁺ T cells in vancomycin-treated mice may have resulted from improved recognition of antigens in tumors, an idea supported by the fact that vancomycin treatment elevated local tumor-associated antigen cross-presentation in tumors and tumors' draining lymph nodes. Notably, treatment with butyrate—the conjugate base of butyric acid, a short-chain fatty acid (SCFA) produced by some gut microbes that are also targets of vancomycin—reduced the activity of antigen-presenting cells in vitro and eliminated the increase in antitumor activity seen when vancomycin treatment was added to radiotherapy. Aligning with this finding, treatment with vancomycin alone or in combination with radiotherapy substantially reduced concentrations of butyrate and the populations of known SCFA-producing bacteria in the cecum contents and stool of mice. In summary, this study provides evidence for an effect of the gut microbiota on response to radiotherapy along with a mechanistic explanation, and the group is currently testing the implementation of vancomycin in non–small cell lung cancer in an actively recruiting phase I clinical trial.

Uribe-Herranz M, Rafail S, Beghi S, Gil-de-Gómez L, Verginadis I, Bittinger K, et al. Gut microbiota modulate dendritic cell antigen presentation and radiotherapy-induced antitumor immune response. J Clin Invest 2020;130:466–79.

• ©2020 American Association for Cancer Research.