Intrinsic Tumor Cell Consequences of Acquired Resistance to PD-L1 Blockade

The use of immune checkpoint inhibitors (ICIs) that block programmed cell death protein ligand 1 (PD-L1) binding to PD-1 have led to durable responses in multiple cancer types; however, a subset of patients eventually stop responding. Currently, few preclinical models faithfully recapitulate clinically-relevant acquired ICI resistance that could help identify second-line treatments. Here we describe the in vivo derivation of cells from orthotopically implanted mouse mammary EMT-6 primary tumors in mice that were initially responsive to PD-L1 inhibition but eventually developed resistance. Transcriptomic comparisons of in vivo-derived parental (EMT6P) and anti-PD-L1 resistant (EMT6PDR) cells revealed alterations in multiple signaling pathways controlling secretory profiles that govern metastasis and angiogenesis. Using a small molecule screen of ~1500 FDA approved cancer drugs, we found that anti-proliferative activity in EMT6PDR cells was decreased for ~120 compounds, including numerous receptor tyrosine kinase inhibitors (RTKIs) currently being tested in ICI-refractory patient populations. Molecular analysis indicated resistance-mediated secretory changes may be linked to intrinsic functions of PD-L1 on the resistant tumor cell which, in turn, may explain differential RTKI sensitivity. Subsequent studies show that EMT6PDR secretory changes can be interferon (IFN) mediated. Together, these results reveal that acquired resistance to PD-L1 blockade can result in PD-L1-regulated intrinsic tumor cell changes involving secretory proteins and controlled, at least in part, by IFN signaling. Current studies seek to assess the impact of these cellular changes on RTKI responsiveness to identify secondary treatments after ICI failure. Citation Format: Yuhao Shi, Michalis Mastri, Melissa Dolan, Michael Oberst, John Ebos. Intrinsic Tumor Cell Consequences of Acquired Resistance to PD-L1 Blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4099.