Immunomodulatory effect of peritumorally administered interferon-beta on melanoma through tumor-associated macrophages

An imbalance of immunosuppressive cells and cytotoxic cells plays an important role in the tumor-bearing host. Together with regulatory T cells (Tregs), tumor-associated macrophages (TAMs) play roles in maintaining the tumor microenvironment. Since interferon beta (IFN-beta) has been clinically used for the treatment of malignant melanoma, we investigated the immunomodulatory effect of IFN-beta during melanoma growth to elucidate the effects of IFN-beta on the tumor microenvironment by using the B16F10 melanoma model. Peritumorally administered IFN-beta significantly decreased the mRNA expression and production of Th2-related chemokines, which suppressed the recruitment of Tregs in B16F10 melanoma. Since the administration of IFN-beta augments the expression of PD-1 on TILs, the co-administration of anti-PD-1 Ab augmented the therapeutic effect of IFN-beta for the treatment of B16F10 melanoma. Moreover, in parallel with the mouse model, in the human system, IFN-beta decreased the production of Th2-related chemokines and augmented the production of Th1-related chemokines from monocyte-derived M2 macrophages. Since these immunomodulatory effects of IFN-beta on macrophages were also observed in the lesional skin of human in-transit melanoma, our present data suggest one of the possible immunomodulatory effects of IFN-beta and support the possibility of IFN-beta in combination with anti-PD-1 Ab for the treatment of melanoma.