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

• Type I IFNs are essential and sufficient for Ab-mediated tumor regression
• Type I IFNs target DCs to improve cross-priming for CTLs
• Type I IFNs are required for overcoming Ab resistance through an extrinsic mechanism
• Anti-PD-L1 Ab can synergize with type I IFNs to cure tumors

SummaryAntibodies (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. Herein we armed the Ab with IFNβ and observed that it is more potent than the first generation of Ab for controlling Ab-resistant tumors. This strategy controls Ab resistance by rebridging suppressed innate and adaptive immunity in the tumor microenvironment. Mechanistically, Ab-IFNβ therapy primarily and directly targets intratumoral dendritic cells, which reactivate 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. This study establishes a next-generation Ab-based immunotherapy that targets and eradicates established Ab-resistant tumors.