Eph tyrosine kinase receptors and their ligands, ephrin, are ubiquitously expressed in many tissues and organs and play important physiological functions as represented by neural and vascular development. In pathological settings, expression analysis using clinical samples of cancer patients shows that the Eph/ephrin system significantly contributes to tumor growth and poor prognosis in many types of cancer such as colorectal and liver cancer. A recent study has showed that EphA10 regulates the expression of PD-L1, an immune check point molecule, in some breast cancer cell lines. Accordingly, we checked if other Ephs are involved in regulation of PD-L1 expression in human cancer tissues and analyzed the expression of Ephs and ephrins in lung cancer using TCGA data set. In lung squamous cell carcinoma, EphA2 is positively correlated with PD-L1 expression, whereas EphA2 is negatively correlated with PD-L1 expression in lung adenocarcinoma. Moreover, a negative correlation was found between ephrin-A1 and PD-L1 expression in lung adenocarcinoma. We are currently investigating the molecular mechanisms in regulation of PD-L1 expression mediated by the Eph/ephrin system.