Combined blockade of IL-6 and PD-1/PD-L1 signaling abrogates mutual regulation of their immunosuppressive effects in the tumor microenvironment

Recently emerging cancer immunotherapies combine the applications of therapeutics to disrupt the immunosuppressive conditions in tumor-bearing hosts. In this study, we found that targeting the pro-inflammatory cytokine interleukin (IL)-6 enhances tumor-specific Th1 responses and subsequent anti-tumor effects in tumor-bearing mice. IL-6 blockade upregulated expression of the immune checkpoint molecule programmed death-ligand 1 (PD-L1) on melanoma cells. This PD-L1 induction was canceled in IFN-gamma-deficient mice or CD4+ T cell-depleted mice, suggesting that CD4+ T cell-derived IFN-gamma is important for PD-L1 induction in tumor-bearing hosts. In some patients with melanoma, however, treatment with the anti-PD-1 antibody Nivolumab increased systemic levels of IL-6, which was associated with poor clinical responses. This PD-L1 blockade-evoked induction of IL-6 was reproducible in melanoma-bearing mice. We found that PD-1/PD-L1 blockade prompted PD-1+ macrophages to produce IL-6 in the tumor microenvironment. Depletion of macrophages in melanoma-bearing mice reduced the levels of IL-6 during PD-L1 blockade, suggesting macrophages are responsible for the defective CD4+ Th1 response. Combined blockade of the mutually regulated immunosuppressive activities of IL-6 and PD-1/PD-L1 signals enhanced expression of T cell-attracting chemokines and promoted infiltration of IFN-gamma-producing CD4+ T cells in tumor tissues, exerting a synergistic anti-tumor effect, while PD-L1 blockade alone did not promote Th1 response. Collectively, these findings suggest that IL-6 is a rational immunosuppressive target for overcoming the narrow therapeutic window of anti-PD-1/PD-L1 therapy.

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