Antifungals improve anti-PD1 efficacy in a murine breast cancer model

Abstract

Abstract 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.