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

Type I interferons (IFNs) are immune-stimulatory cytokines involved in antiviral and antitumor immune responses. They enhance the efficacy of immunogenic anticancer therapies by activating both innate and adaptive intratumoral immune cell populations. 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 a murine melanoma mouse model. We describe a pro-inflammatory and M1-like TAM phenotype induced by tumoral IFNβ and identify a myeloid type I interferon-response signature associated with a high M1/M2 TAM ratio and an increased overall survival in previously irradiated patients with MBMs. We provide evidence that tumoral IFNβ supports an effective antitumor immune response by re-educating immune-regulatory TAMs. These findings uncover type I interferon-dependent 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.