Soluble Pd-L1 As A Surrogate Biomarker Of Metastatic Progression And Resistance To Antiangiogenic Therapy

Immune-checkpoint inhibitors are now approved for the treatment of early- and late-stage cancers. These include agents that block the T-cell regulatory protein programmed cell death 1 (PD-1) from being activated by the PD-1 ligand 1 (PD-L1) expressed on cancer cells. There is an urgent need to identify biomarkers of PD-1 pathway inhibition that would predict patient populations responsive to treatment and/or serve as surrogates for drug activity and resistance. PD-L1 expression on tumors is currently a biomarker candidate, but reliable detection and quantification methodologies have proven challenging to standardize. Recently, a soluble PD-L1 (sPD-L1) fragment was identified that can derive from cell-bound PD-L1. Retrospective clinical examinations of sPD-L1 levels in cancer patients suggest a potential use as a surrogate for disease progression and response to treatment; but few preclinical studies have been performed to test this predictive value. We undertook experiments to evaluate plasma sPD-L1 in mouse tumor models during localized primary tumor growth (after orthotopic cell implantation) and spontaneous metastatic disease progression (after surgical removal of the primary). Mouse syngeneic and human xenograft implantation models included breast, kidney, colon, and melanoma cell systems. Our results show that circulating plasma sPD-L1 can correlate with primary and metastatic progression in a stage and model specific manner. Next, we evaluated sPD-L1 following treatment with neutralizing antibodies to PD-1 and PD-L1 in tumor-free mice and found significant dose-dependent sPD-L1 increases, suggesting systemic changes may have utility as a measurement of target saturation and dosing independent of tumor growth. Finally, with current approvals of PD-1 inhibitors in renal cell carcinoma (RCC) patients previously treated with antiangiogenic agents that block vascular endothelial growth factor (VEGF), we evaluated plasma in mouse models of sunitinib resistance - a VEGF receptor tyrosine kinase inhibitor (RTKI). Our results demonstrate that VEGF pathway resistance yields changes in sPD-L1 and may be useful in predicting response to PD-1 pathway inhibition in the refractory setting. Together, these investigations suggest that circulating sPD-L1 changes during disease progression (both local and disseminated) may serve as a potential predictive biomarker for immune-checkpoint and antiangiogenic therapy. Citation Format: Michalis Mastri, Amanda Tracz, Yuhao Shi, Georg Bjarnason, Tran Nguyen, Brian Rini, John M.L. Ebos. Soluble PD-L1 as a surrogate biomarker of metastatic progression and resistance to antiangiogenic therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5599. doi:10.1158/1538-7445.AM2017-5599