397PD KRAS mutation-induced upregulation of PD-L1 mediates immune escape in lung adenocarcinoma

Abstract

Background Programmed death-ligand 1 (PD-L1) expression is associated with EGFR mutation and EML4-ALK rearrangement. Whether PD-L1 is regulated by other driver mutations like KRAS in lung adenocarcinoma and what is the molecular mechanism remain largely unknown. Methods In the present study, western-blot, real-time PCR, flow cytometry and immunofluorescence were employed to explore how PD-L1 was regulated by KRAS mutation. Relevant inhibitors were used to identify the downstream signaling pathways involved in PD-L1 regulation. Cell apoptosis, viability and Elisa test were used to study the immune suppression by KRAS mutation and immune reactivation by ERK inhibitor and/or PD-1 blocking in tumor cells and T cells co-culture system. Results We found that PD-L1 expression was correlated with KRAS mutation in the cell lines and human tissue of lung adenocarcinoma. PD-L1 was up-regulated by KRAS mutation through p-ERK but not p-AKT signaling.We also found that KRAS-mediated up-regulation of PD-L1 induced the apoptosis of CD3-positive T cells which was reversed by pembrolizumab or ERK-specific inhibitor. Blocking PD-1 by anti-PD-1 antibody or PD-L1 by ERK inhibitor could re-activate the anti-tumor immunity of T cells and decrease the survival rates of KRAS-mutant NSCLC cells in co-culture system in vitro. However, we did not observe the synergistic effect of pembrolizumab and ERK inhibitor together on killing of tumor cells in co-culture system. Conclusions Our study demonstrates that KRAS mutation induces PD-L1 expression through p-ERK signaling in lung adenocarcinoma. Therapy targeting PD-1/PD-L1 axis provides a promising treatment option for KRAS-mutant lung adenocarcinoma. Legal entity responsible for the study Sun Yat-sen University Cancer Center Funding Sun Yat-sen University Cancer Center Disclosure All authors have declared no conflicts of interest.