Radiation continues to play a major role in the treatment of almost every cancer type. Traditional radiation studies focused on its ability to damage DNA, but recent evidence has demonstrated that a key mechanism driving the efficacy of radiation in vivo is the immune response triggered in irradiated tissue. Innate immune cells including macrophages, dendritic cells, and natural killer cells are key mediators of the radiation-induced immune response. They regulate the sensing of radiation-mediated damage and subsequent radiation-induced inflammation. Given the importance of innate immune cells as determinants of the post-radiation anti-tumor immune response, much research has been devoted to identify ways to both enhance the innate immune response and prevent their ability to suppress ongoing immune responses. In this review, we will discuss how the innate immune system shapes anti-tumor immunity following radiation and highlight key strategies directed at the innate immune response to enhance the efficacy of radiation.
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.
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