Acquired resistance to PD-L1 inhibition is associated with an enhanced type I IFN-stimulated secretory program in tumor cells

BackgroundInterferon (IFN) pathway activation in tumors can have dual, sometimes opposing, influences on immune responses. Therapeutic inhibition of programmed cell death ligand (PD-L1) - a treatment that reverses PD-1-mediated suppression of tumor-killing T-cells - is linked to alterations in IFN signaling; however, less is known about the role of IFNs after treatment resistance. Since IFN-regulated intracellular signaling can control extracellular secretory programs in tumors to modulate immunity, we examined the consequences of PD-L1 blockade on IFN-related secretory changes in preclinical models of acquired resistance. MethodsTherapy-resistant cell variants were derived from orthotopically grown mouse tumors initially sensitive or insensitive to PD-L1 antibody treatment. Cells representing acquired resistance were analyzed for changes to IFN-regulated secretory machinery that could impact tumor progression. ResultsWe identified a PD-L1 treatment-induced secretome (PTIS) that was enriched for several IFN-stimulated genes (ISGs) and significantly enhanced when stimulated by type I IFNs (IFN or IFN{beta}). Secretory changes were specific to treatment-sensitive tumor models and found to suppress activation of T cells ex vivo while diminishing tumor cell cytotoxicity, revealing a tumor-intrinsic treatment adaptation with potentially broad tumor-extrinsic effects. When reimplanted in vivo, resistant tumor growth was slowed by the blockade of individual secreted PTIS components (such as IL6) and stopped altogether by a more generalized disruption of type I IFN signaling. In vitro, genetic or therapeutic methods to target PD-L1 could only partially recapitulate the IFN-enhanced PTIS phenotype, showing that in vivo-based systems with intact tumor:immune cell interactions are needed to faithfully mimic acquired resistance as it occurs in patients. ConclusionsThese results suggest that prolonged in vivo PD-L1 inhibition can rewire type I IFN signaling to drive secretory programs that help protect tumors from immune cell attack and represent a targetable vulnerability to overcome acquired resistance in patients.