Commensal Bacteria and Fungi Influence Response to Radiation Therapy

The composition and homeostasis of the human gut microbiome is implicated in cancer outcomes, including tumor development, progression, and response to therapies. Preliminary analyses have implicated the gut microbiome in modulating the efficacy of both chemotherapy and immunotherapy, but little work has been done investigating how these commensal microorganisms affect response to radiation therapy. Using orthotopic mouse models of breast cancer and melanoma, Shiao, Kershaw, and colleagues showed that depletion of commensal bacteria by antibiotic treatment reduced the ability of radiation therapy to delay tumor growth and increase survival, with further analysis of the tumors showing more proliferating cells and reduced cell death compared to antibiotic-naïve mice. Conversely, specific depletion of commensal fungi improved response to radiation therapy in tumor-bearing mice, delaying tumor growth, increasing cell death, and improving survival. After radiation therapy, depletion of commensal bacteria increased the frequency of CD11b⁺ tumor-associated macrophages but had no effect on CD4⁺ or CD8⁺ T cells, whereas antifungal treatment depleted CD4⁺ T cells and increased CD8⁺ T cells, with no effect on macrophages. Antibiotic treatment in non–tumor-bearing mice led to a dominant overgrowth of fungi from the Saccharomycetales order, including Saccharomyces and Candida. Colonization of tumor-bearing mice with Candida albicans resulted in faster tumor growth and poorer survival after radiation therapy and generated a more immunosuppressive environment, characterized by an increased ratio of PD-1⁺ CD8⁺ T cells. Treatment with an antifungal drug depleted Candida and restored response to radiation therapy, reducing PD-1⁺ CD8⁺ T cells and cell proliferation and improving survival. Mice generated to harbor no commensal fungi showed similar results. Analysis of human breast tumors revealed high expression of the fungal-recognition protein Dectin-1, and immune cells expressing higher levels of Dectin-1 were associated with poorer survival. Dectin-1–deficient mice had an enhanced response to radiation therapy, and tumor-associated macrophages were shown to sense fungi via Dectin-1. Collectively, these preclinical findings raise the possibility that manipulating the gut microbiome could improve response to radiation therapy.

Shiao SL, Kershaw KM, Limon JJ, You S, Yoon J, Ko EY, et al. Commensal bacteria and fungi differentially regulate tumor responses to radiation therapy. Cancer Cell 2021 Jul 29 [Epub ahead of print].

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