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

Therapeutic inhibition of programmed cell death ligand (PD-L1) can reverse PD-1-mediated suppression of tumor-killing T-cells; however, many patients develop resistance. Acquired resistance may be derived from intracellular PD-L1 and interferon(IFN) signaling programs in the tumor that can have dual, sometimes opposing, influences on tumor immune responses. Here we show that PD-L1 inhibition induces a novel secretory program tightly controlled by IFN-signaling and specific to acquired, but not innate, resistance in tumors. A PD-L1 treatment-induced secretome (PTIS) was found to be enriched for several IFN-stimulated genes (ISGs) and then further enhanced by type I IFN stimulation (IFN or IFN{beta}) in multiple mouse tumor models. Chronic inhibition or gene knockout of tumor PD-L1 in vitro could elicit similar type I IFN-enhanced secretory stimulation while resistant cells were able to suppress T cell activation and killing ex vivo. When reimplanted into mice, resistant tumors were more sensitive to IL-6 inhibition (a key PTIS component) and growth significantly reduced when type I IFN signaling was blocked. Together, these results show that prolonged PD-L1 inhibition can rewire existing intracellular IFN:PD-L1 signaling crosstalk to drive secretory programs that help protect tumors from immune cell attack and represent a targetable vulnerability to overcome acquired resistance in patients.