Diverse Anti-Tumor Immune Potential Driven by Individual IFNα Subtypes

Immunotherapies harnessing T cell immunity have shown remarkable clinical success for the management of cancer. However, only a proportion of patients benefit from these treatments. The presence of type I interferon (IFN) within the tumor microenvironment is critical for driving effective tumor-specific T cell immunity. Individuals can produce 12 distinct subtypes of IFN alpha, which all signal through a common receptor. Despite reported differences in anti-viral potencies, the concept that distinct IFN alpha subtypes can improve anti-cancer treatments remains unclear. We tested whether expression of unique IFN alpha subtypes confined to the tumor microenvironment enhances tumor control. This was systematically evaluated by transplantation of B16 murine melanoma cells secreting five unique IFN alpha subtypes (B16_IFN alpha 2; B16_IFN alpha 4; B16_IFN alpha 5; B16_IFN alpha 6; B16_IFN alpha 9) into a pre-clinical murine model. We show that IFN alpha 2 and IFN alpha 9 are the only subtypes capable of completely controlling tumor outgrowth, with this protection dependent on the presence of an adaptive immune response. We next determined whether these differences extended to other model systems and found that the adoptive transfer of tumor-specific CD8(+) T cells engineered to secrete IFN alpha 9 delays tumor growth significantly and improves survival, whereas no enhanced survival was observed using T cells secreting IFN alpha 4. Overall, our data shows that the expression of distinct IFN alpha subtypes within the tumor microenvironment results in different anti-tumor activities, and differentially affects the efficacy of a cancer therapy targeting established disease.