Using syngeneic breast cancer and melanoma models in SPF-housed mice, Shiao and Kershaw et al. showed that the efficacy of radiotherapy that avoids gut exposure (RT) was reduced by administering antibiotic cocktails that depleted bacteria, but expanded gut fungi, and increased suppressive TAMs. Anti-fungal treatment increased RT effects and granzyme B+ CD8+ T cells, and reduced PD-1+ T cells and suppressive macrophages. RT efficacy was enhanced in fungi-free mice and in mice deficient for Dectin-1, an innate immune sensor of β-glucans on fungi. Human breast tumors expressed Dectin-1; higher levels were associated with worse survival.
Contributed by Paula Hochman
ABSTRACT: Studies suggest that the efficacy of cancer chemotherapy and immunotherapy is influenced by intestinal bacteria. However, the influence of the microbiome on radiation therapy is not as well understood, and the microbiome comprises more than bacteria. Here, we find that intestinal fungi regulate antitumor immune responses following radiation in mouse models of breast cancer and melanoma and that fungi and bacteria have opposite influences on these responses. Antibiotic-mediated depletion or gnotobiotic exclusion of fungi enhances responsiveness to radiation, whereas antibiotic-mediated depletion of bacteria reduces responsiveness and is associated with overgrowth of commensal fungi. Further, elevated intratumoral expression of Dectin-1, a primary innate sensor of fungi, is negatively associated with survival in patients with breast cancer and is required for the effects of commensal fungi in mouse models of radiation therapy.
Author Info: (1) Department of Radiation Oncology, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA; Department of Biomedical Sciences, Cedars-Sinai Medical Cente
Author Info: (1) Department of Radiation Oncology, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. Electronic address: stephen.shiao@cshs.org. (2) Department of Radiation Oncology, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA; F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. (3) F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. (4) Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. (5) Department of Radiation Oncology, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA. (6) Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. (7) Genomics Core, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. (8) Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
