Targeting the Tumor Microenvironment with Interferon-β Bridges Innate and Adaptive Immune Responses

Abstract

SUMMARY Antibodies (Abs) that preferentially target oncogenic receptors have been increasingly used for cancer therapy, but tumors often acquire intrinsic Ab-resistance after prolonged and costly treatment. Here, we arm the Ab with IFNβ and observed that it is more potent than first generation of Ab for controlling Ab-resistant tumors. This strategy controls Ab-resistance by rebridging suppressed innate and adaptive immunity in tumor microenvironment. Mechanistically, Ab-IFNβ therapy primarily and directly targets intra-tumoral dendritic cells, which re-activate CTL by increasing antigen cross presentation within the tumor microenvironment. Additionally, blocking PD-L1, which is induced by Ab-IFNβ treatment, overcomes treatment-acquired resistance and completely eradicates established tumors. Therefore, this study establishes a nextgeneration Ab-based immunotherapy that targets and eradicates established Ab-resistant tumors.

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

“…As one strategy to boost this type I IFN production in the tumor microenvironment, we generated conjugates of IFN-b coupled to tumor-targeting mAbs. Systemic administration of these agents could deliver transient low levels of IFN-b to tumor sites, which supported tumor control in a T cell-dependent fashion (9). Conditional type I IFNR gene-targeted mice revealed an essential role for type I IFN signaling on CD11c + host DCs with that approach, consistent with the mechanism by which endogenous type I IFNs promote antitumor immunity.…”

Type-I-interferons in infection and cancer: Unanticipated dynamics with therapeutic implications

“…In addition, Type-I-IFNs boosted the antineoplastic activity of antibodies specific for oncogenic receptors, such as epidermal growth factor receptor (EGFR) and human EGFR (HER)2, mobilizing DCs to cross-present TAAs to CTLs. 74 However, despite these observations strongly support the antitumor and immune-stimulatory effects of Type-I-IFNs, paradoxical proofs of a dichotomous, detrimental tumor growth-promoting role for these cytokines are also reported. In this context, some harmful effects seem to depend on the ability to induce immune-checkpoint pathways as a major mechanism of immune resistance, particularly against CTLs specific for TAAs.…”

“…In this context, some harmful effects seem to depend on the ability to induce immune-checkpoint pathways as a major mechanism of immune resistance, particularly against CTLs specific for TAAs. As reported above, Type-I-IFNs upregulate PD-L1 in tumor cells, 2,74 which can lead to T cell exhaustion. 109 It remains a central goal of studies on tumor immunity to elucidate the multitude of molecular nets activated by Type-I-IFNs.…”

“…72 This phenomenon was mainly due to Type-I-IFN-induced accumulation of reactive oxygen species (ROS). 73 Additional indirect proofs of the tumor growth promoting role of Type-I-IFNs come from recent studies showing that, in cancer cells, Type-I-IFNs upregulated the ISG programmed death-ligand (PD-L)1 74 (panel 8, Fig. 2).…”

Facilitating T Cell Infiltration in Tumor Microenvironment Overcomes Resistance to PD-L1 Blockade

“…Given the limitations of a therapeutic that requires local delivery to patients, and that systemic injections of immune cytokine can often lead to dose-dependent side effects, we wanted to develop a system that can provide targeted delivery of LIGHT (Yang et al, 2014).…”