Targeting Type I Ifn-Regulated Secretory Profiles To Overcome Acquired Anti-Pd-L1 Resistance.

Abstract Therapeutic inhibition of PD-L1 has led to durable benefits for many cancer patients; however, acquired resistance is common. Dysregulated type I and II interferon (IFN) signalling on tumor cells can contribute to resistance via altered expression of IFN stimulated genes (ISGs) leading to immune-suppression and tumor promotion. In this study, we examined the role of type I IFN signaling following acquired resistance to PD-L1 blockade using an EMT6 mouse breast orthotopic tumor model that was initially responsive to treatment, but that later relapsed. Following selection of PD-L1 drug resistant (PDR) tumor cells, transcriptomic and proteomic analysis was used to identify a unique signature of secreted proteins associated with IFN signaling that was then validated using published preclinical and clinical datasets. Using genetic and therapeutic approaches to block PD-L1 in vitro, we found PDR secretory signatures to be enhanced after type I IFN stimulation. In vivo, inhibition of specific ISGs (IL-6) or ISG regulators (IFNAR1) led to enhanced anti-tumor effects in PDR models, compared to parental controls. Together, these results identify a secretory profile associated with acquired resistance to PD-L1 blockade that may be modulated, in part, by a tumor-intrinsic PD-L1/IFN signaling crosstalk and suggest that selective targeting of secreted ISGs may provide benefit for patients after anti-PD-L1 treatment failure. Citation Format: Yuhao Shi, Melissa Dolan, Michalis Mastri, James W. Hill, Kevin Eng, John M. Ebos. Targeting type I IFN-regulated secretory profiles to overcome acquired anti-PD-L1 resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1644.