P17.28.A TUMORAL INTERFERON BETA INDUCES AN IMMUNE-STIMULATORY PHENOTYPE IN TUMOR-ASSOCIATED MACROPHAGES IN MELANOMA BRAIN METASTASES

Abstract BACKGROUND Type I interferons (IFN) such as IFNβ are pro-inflammatory cytokines involved in antiviral immune responses. Increasing evidence indicates that the success of several anticancer therapies, including radiotherapy, relies on the immune-stimulatory effects of type I IFNs on innate and adaptive immune cells in the tumor microenvironment (TME). Tumor-associated macrophages (TAMs) are one of the most abundant innate immune cells in the TME of melanoma brain metastases (MBMs) and can exert potent immune-suppressive functions compromising effective antitumor immune responses. Here, we investigate the potential of tumoral type I IFNs to re-educate TAMs towards an antitumor M1-like phenotype to enhance the efficacy of immunogenic anticancer therapies in MBMs. MATERIAL AND METHODS In order to minimize confounding effects of immunogenic cell death associated with type I IFN-dependent anticancer therapies, we generated an inducible IFNβ-overexpressing MBM mouse model. Tumor growth was measured by magnetic resonance imaging (MRI) and changes in the TME were analyzed by flow cytometry. We confirmed our in vivo findings by mixed-leukocyte reaction assay and RNA sequencing of IFNβ-treated bone marrow-derived macrophages (BMDMs) and validated our myeloid type I IFN-response signature gene set in a recently published RNA sequencing dataset of treatment-naïve and previously irradiated MBM patient samples. RESULTS In this murine MBM model, tumoral IFNβ markedly impaired tumor growth and TAMs from IFNβ-expressing tumors exhibited a decreased expression of CD206, a widely used marker for immune-regulatory M2-like macrophages. Functional and transcriptomic analyses of IFNβ-treated BMDMs revealed an immune-stimulatory M1-like phenotype. Following radiotherapy, the myeloid type I IFN-response signature was upregulated in over 40 percent of MBM patient samples which was associated with a higher M1/M2-like TAM ratio and increased overall survival. CONCLUSION Our findings demonstrate the immune-stimulatory capacity of tumoral IFNβ in the context of type I IFN-inducing anticancer therapies in MBM by re-polarizing TAMs towards a pro-inflammatory M1-like phenotype.