Influence of Bacterial Metabolites on the Systemic Antitumor Immune Response after Radiation Therapy in Combination with Immune Checkpoint Inhibitors

Abstract

The gut microbiome influences the pathogenesis of many diseases and numerous medical therapies. In addition, it is well known that cancer patients are often treated with antibiotics during the course of their disease, which can lead to intestinal dysbiosis. Importantly, experimental and clinical studies have already shown that this has implications for tumor therapies and that immune-active bacterial metabolites can play a central mechanistic role. However, little is known about the influence of the bacterial microbiota or its metabolites on the outcome of radiotherapy (RT) in combination with immune checkpoint inhibitors (ICIs). We used a bilateral tumor model (MC38 tumor cells) to investigate the influence of the intestinal microbiota and selected bacterial metabolites on the abscopal effect after RT in combination with ICIs. In brief, RT (1 × 8 Gy) of the right tumor was performed 7 days after tumor induction, followed by application of α-CTLA4 or α-PD1 for three weeks. Antibiotics (ampicillin, neomycin, metronidazole, and vancomycin) or selected immune-activating metabolites were administered daily by gavage. We used bacterial metabolites that are described in the literature as having strong immune-modulating properties. In mice, combined treatment with different antibiotics had neither a significant effect on tumor growth of the irradiated tumor nor on tumor progression of the unirradiated tumor after RT in combination with α-CTLA4. In contrast, supplementation of specific bacterial metabolites had different effects depending on the type of ICI and the specific type of bacterial metabolite. Specifically, we identified bacterial metabolites that led to enhanced tumor progression of the unirradiated abscopal tumor after RT combined with ICIs, resulting in reduced survival rates. To the best of our knowledge, we are presenting here for the first-time experimental data on the influence of the intestinal microbiome on the abscopal effect after RT combined with ICIs. Our data clearly show that specific immune-active bacterial metabolites can negatively influence the abscopal effect after combined radioimmunotherapy. This implies the design of further experimental studies aimed at using specific strategies (e.g., antibiotics) to decimate certain gut bacteria and reduce the amount of certain bacterial metabolites to improve response rates after radioimmunotherapy.