Abstract A153: Targeting DNA damage response upregulates PD-L1 level and promotes antitumor immunity in small-cell lung cancer

Abstract

Purpose of the Study: Despite recent advances in the use of immunotherapy, only a minority of small cell lung cancer (SCLC) patients respond to immune checkpoint blockade (ICB) with programmed cell death protein 1 (PD-1) or programmed death ligand 1 (PD-L1) antibodies as monotherapy or combination. Therefore, there is a critical need to develop strategies to enhance the efficacy of ICB in SCLC, an otherwise immunosuppressed disease with dismal 5-year survival rate of 30 years. We have previously shown that prexasertib and olaparib treatment enhanced the protein (but not mRNA) and surface expression of PD-L1 in SCLC cell lines and tumor models. Here we elucidate the previously unexplored mechanism of how DNA damage response targeting enhances antitumor immunity in SCLC. Methods: SCLC cell lines and immune competent murine models were treated with inhibitors targeting DNA damage repair (DDR) proteins, checkpoint kinase 1 (CHK1) (by prexasertib), poly (ADP-ribose) polymerase (PARP) (by olaparib) either as single agents or in combination with anti-PD-L1. End point analyses were done by Western blot, real-time RT-PCR, multicolor flow cytometry and reverse phase protein array (RPPA). Result: We observed increased PD-L1 glycosylation post-prexasertib and olaparib treatment. Prexasertib and/or olaparib +/- anti-PD-L1 combination activates mTOR and inactivates GSK3β pathway thus providing mechanistic insight into DDR-targeting mediated PD-L1 glycosylation and stabilization. We treated tumor-bearing immune-competent B6129F1 mice with either IgG (control), prexasertib (10mg/kg, 2/7), anti-PD-L1 (300ug, 1/7) or combination (n=10/group). At Day 21, anti-PD-L1 did not cause tumor regression and prexasertib treatment delayed tumor growth [T/C=0.31(p Citation Format: Triparna Sen, Bertha Leticia Rodriguez, Limo Chen, Naoto Morikawa, Junya Fujimoto, Lixia Diao, Youhong Fan, Jing Wang, Bonnie S. Glisson, Ignasio Wistuba, Julien Sage, John V. Heymach, Don L. Gibbons, Lauren A. Byers. Targeting DNA damage response upregulates PD-L1 level and promotes antitumor immunity in small-cell lung cancer [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A153.