Tumoral Interferon Beta Induces an Immune-Stimulatory Phenotype in Tumor-Associated Macrophages in Melanoma Brain Metastases

Abstract

Abstract Type I interferons (IFN) are immune-stimulatory cytokines involved in antiviral and antitumor immune responses. They enhance the efficacy of immunogenic anticancer therapies such as radiotherapy by activating both innate and adaptive immune cells. Macrophages are one of the most abundant innate immune cells in the immune microenvironment of melanoma brain metastases (MBMs) and can exert potent immune-suppressive functions. Here, we investigate the potential of tumoral type I IFNs to re-polarize tumor-associated macrophages (TAMs) in two murine MBM models and assess the effects of radiotherapy-induced type I IFNs on TAMs in a transcriptomic MBM patient dataset. In mice, we describe a pro-inflammatory M1-like TAM phenotype induced by tumoral IFNβ and identify a myeloid type I IFN-response signature associated with a high M1/M2-like TAM ratio. Following irradiation, patients with MBMs displaying a myeloid type I IFN-response signature showed increased overall survival, providing evidence that tumoral IFNβ supports an effective antitumor immune response by re-educating immune-regulatory TAMs. These findings uncover type I IFN-inducing therapies as a potential macrophage-targeting therapeutic approach and provide a rationale for combining radiotherapy with concomitant immunotherapy to improve treatment response in patients with MBM.