Acquired resistance to PD-L1 inhibition enhances a type I IFN-regulated secretory program in tumors.

Therapeutic inhibition of programmed cell death ligand (PD-L1) is linked to alterations in interferon (IFN) signaling. Since IFN-regulated intracellular signaling can control extracellular secretory programs in tumors to modulate immunity, we examined IFN-related secretory changes in tumor cells following resistance to PD-L1 inhibition. Here we report an anti-PD-L1 treatment-induced secretome (PTIS) in tumor models of acquired resistance that is regulated by type I IFNs. These secretory changes can suppress activation of T cells ex vivo while diminishing tumor cell cytotoxicity, revealing that tumor-intrinsic treatment adaptations can exert broad tumor-extrinsic effects. When reimplanted in vivo, resistant tumor growth can slow or stop when PTIS components are disrupted individually, or when type I IFN signaling machinery is blocked. Interestingly, genetic and therapeutic disruption of PD-L1 in vitro can only partially recapitulate the PTIS phenotype highlighting the importance of developing in vivo-based resistance models to more faithfully mimic clinically-relevant treatment failure. Together, this study shows acquired resistance to immune-checkpoint inhibitors 'rewires' tumor secretory programs controlled by type I IFNs that, in turn, can protect from immune cell attack.