Despite the advent of targeted therapies and breakthrough immunotherapies, lung cancer remains the number one cause of cancer-related death. Immune checkpoint inhibitors against PD-1 and PD-L1 induce remarkable and durable responses in a fraction of NSCLC patients, but most fail to respond or develop intolerable autoimmune-related toxicities. Additionally, the current standard of using PD-L1 expression alone as a biomarker is not strongly predictive of patient response and reveals the challenges that clinicians face when the understanding of the underlying biology lags behind clinical implementation.

EphA2 receptor tyrosine kinase is implicated in many solid tumors, including NSCLC, as well as inflammatory processes. Blockade of EphA2 induces apoptosis in NSCLC cells and increases survival in mouse models of NSCLC, demonstrating that EphA2 is a viable target for therapeutic intervention in NSCLC. Here, we examine how EphA2 in NSCLC cancer cells affects the PD-1 and PD-L1/2 checkpoint signaling axis in the tumor microenvironment. Preliminary studies suggest that EphA2 regulates the expression of PD-L2, but not PD-L1, in normal epithelium, as well as NSCLC cell lines. Knockdown of EphA2 by siRNA in BEAS-2B human bronchial epithelial cells shows decreased surface PD-L2 expression by flow cytometry. Additionally, PD-L2 expression is induced in human NSCLC cell lines by cytokine stimulation, specifically IFNg and IL-4. Knockdown of EphA2 in a subset of KRAS mutant human NSCLC cell lines after cytokine stimulation decreased PD-L2 expression. Analysis of NSCLC surgical specimens and survival data demonstrate that higher PD-L2 expression correlates with worse prognosis.

Despite PD-L2’s known role in immune tolerance, its impact on the tumor microenvironment is greatly understudied compared to PD-L1. Thus, further elucidation of EphA2s role in regulating PD-1 and PD-L2 interactions in functional assays and in in vivo mouse models will further our understanding of PD-1 and PD-L1/PD-L2 biology in the tumor immune microenvironment and will be critical for predicting the effects of immune checkpoint inhibitors.

Citation Format: Eileen F. Shiuan, Shan Wang, Ariel Raybuck, Mark Boothby, Jin Chen. The role of EphA2 receptor tyrosine kinase in antitumor immunity mediated through programmed death ligand 2 (PD-L2) in non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr B58.