Therapeutic Activity of High-Dose Intratumoral IFN-β Requires Direct Effect on the Tumor Vasculature

Abstract

Endogenous type I IFN production after innate immune recognition of tumor cells is critical for generating natural adaptive immune responses against tumors in vivo. We recently have reported that targeting low doses of IFN-β to the tumor microenvironment using tumor-specific mAbs can facilitate antitumor immunity, which could be augmented further with PD-L1/PD-1 blockade. However, sustained high doses of type I IFNs in the tumor microenvironment, which are potently therapeutic alone, may function through distinct mechanisms. In the current report, we demonstrate that high-dose intratumoral type I IFNs indeed exerted a profound therapeutic effect in the murine B16 model, which unexpectedly did not increase T cell responses. Moreover, bone marrow chimeras revealed a role for type I IFN signaling on nonhematopoietic cells, and most of the therapeutic effect was retained in mice deficient in T, B, and NK cells. Rather, the tumor vasculature was ablated with high-dose intratumoral IFN-β, and conditional deletion of IFN-α/βR in Tie2-positive vascular endothelial cells eliminated most of the antitumor activity. Therefore, the major component of the antitumor activity of sustained high doses of type I IFNs occurs through a direct antiangiogenic effect. Our data help resolve conditions under which distinct antitumor mechanisms of type I IFNs are operational in vivo.

Type I interferon–mediated autoimmune diseases: pathogenesis, diagnosis and targeted therapy

“…An interferon signature similar to SLE and myositis was identified in patients with scleroderma (98). Antiphospholipid syndrome was reported as a side effect in patients receiving IFN- therapy for unrelated diseases (101,102). We found that patients with early incomplete forms of connective tissue diseases (of whom a proportion progressed to SLE or other diseases) had increased interferon activity (93).…”

Divergent effects of type-I interferons on regulatory T cells

“…Whether Treg modulation impacts on protective IFN effects remains to be understood. Rather, a recent study has revealed that, in mouse model of high-dose intratumoral IFN injection, the potent anti-tumor effects of the therapy were mostly due to the tumor vasculature ablation [62].…”

Molecular Pathways: Targeting the Stimulator of Interferon Genes (STING) in the Immunotherapy of Cancer

“…The therapeutic effect of low doses of type I IFNs to the tumor microenvironment was shown to be T cell-dependent and mediated through type I IFN signaling on host DCs. However, high doses of intratumoral type I IFN might have mainly an anti-angiogenic effect, which was mediated through the IFNAR on endothelial cells (64, 65). Finally, directed radiation to the tumor site also induces type I IFN production, thereby augmenting T cell priming (66).…”