IFN-β augments the anti-tumor effects of PD-1 Abs in melanoma: The possible immunotherapy for metastatic melanoma

Abstract

Together with regulatory T cells (Tregs), tumor-associated macrophages (TAMs) play roles in maintaining the tumor microenvironment. Since IFNβ has been clinically used for the treatment of malignant melanoma in Japan, first, we investigated its immunomodulatory effects during B16F10 melanoma growth. B16F10 melanoma cells (2 × 105 cells/mouse) were subcutaneously injected into C57BL/6 mice, and when the tumor had reached 5 mm in diameter, we administered IFN-β. We found that peritumoral administration of IFN-β significantly decreased tumorinfiltrating Tregs, using qRT-PCR and flowcytometry analysis. Next, we examined the chemokines in the tumor, which revealed that IFN-β reduced the expression of Tregs-related chemokines (CCL17, CCL22), which led to the suppression of the recruitment of Tregs in B16F10 melanoma. Moreover, to validate the production of chemokines, we isolated CD11b+ cells by MACS, analyzed the chemokine production, and confirmed the decrease of CCL22 in the IFN-β treated group. Since the administration of IFN-β augments the expression of PD-1 on TILs, the co-administration of anti-PD-1 Ab augmented the therapeutic effect of IFN-β on the treatment of B16F10 melanoma. In parallel with the mouse model, in human, IFN-β decreased the production of Th2-related chemokines and augmented the production of Th1-related chemokines from monocyte-derived M 2 macrophages. Since these immunomodulatory effects of IFN-β on macrophages were also observed in the lesional skin of human in-transit melanoma, we started phase Ib study to determine the safety dose of IFN-β in combination with anti-PD1 Ab therapy. Our present data suggest one of the possible use of IFN-β in combination with anti-PD-1 Ab for the treatment of melanoma patients.