New perspectives on type I IFNs in cancer

Abstract

Although type I IFNs were initially described based on their anti-viral properties, it was quickly realized that these cytokines had anti-proliferative and anti-cancer activities. These observations ultimately led to the clinical development and utility of IFN-α2b for the treatment of patients with melanoma, renal cell carcinoma, and chronic myelogenous leukemia, among others. However, the mechanism of action of type I IFNs in vivo was never fully elucidated, and the pleiotropic effects of IFNs on multiple cell types had made it challenging to decipher. Advancement of genetically engineered mouse models has provided new tools for interrogating these mechanisms. Recent evidence has indicated that spontaneous innate immune sensing of cancers that leads to adaptive immune responses is dependent on host type I IFN production and signaling. The major innate immune receptor pathway that leads to type I IFN production in response to a growing tumor appears to be the STING pathway of cytosolic DNA sensing. STING agonists drive type I IFN production and are impressively therapeutic in mouse tumor models. Targeting low doses of type I IFNs to the tumor microenvironment also promotes anti-tumor activity via host adaptive immunity that is T cell-dependent. However, high doses of intratumoral type I IFNs largely function via an anti-angiogenic effect. Understanding these mechanistic details should enable improved clinical manipulation of the type I IFN system in cancer.

Figure 1. Therapeutic mechanisms of intratumoral type I IFNs appears to vary with dose

Low doses of endogenous IFN-β produced in response to innate immune sensing of cancer is upstream from T cell priming and drives an adaptive immune response. Targeting of low doses of IFN-β into tumor sites with mAb conjugation also facilitates induction of T cell responses against tumor antigens. However, high sustained doses of IFN-β, which also has a therapeutic effect, largely works via a T cell-independent mechanism. Instead, a direct anti-angiogenic effect is observed, which is mediated through the type I IFN receptor (IFNAR) expressed by endothelial cells.