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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.

Every year over 200,000 North American women are diagnosed with breast cancer, which is the second leading cause of cancer death among women. The introduction of effective immunotherapies has revolutionized patient care in many cancers, including breast, but only a subset of patients exhibit clinical response. Factors determining a patient’s response to immunotherapy is an area of intense research. The microbiome is one potential contributing factor. The human intestinal microbiome is comprised largely of bacteria, but also harbors fungi, viruses and archaea that undoubtedly have significant biological functions. Recent reports have detailed the association of specific strains of bacteria with positive response to PD-1/PDL1 therapy in several cancers however, little is known regarding the involvement of commensal fungi. Previous work in our lab found a high diversity of fungi associated with the human gut, which interact with the immune system and influence the severity of gastrointestinal inflammation and allergic airway disease. Using a syngeneic murine model of triple negative breast cancer, we found that antifungal treatment sensitizes previously resistant tumors to anti-PD1 therapy, leading to a significant decrease in growth rate as well as increased survival compared to anti-PD-1 treatment alone. Antifungal treatment altered the microbiome composition as evidenced by 16s and ITS1 sequencing of fecal pellets, as well as altered the tumor immune compartment to promote anti-tumor activity when combined with anti-PD1. These data suggest fungi have a role in shaping the immune-tumor microenvironment and provide insight into how perturbation of the microbiome might improve response to immunotherapy.