KRAS mutants to regulate PD-L1 expression through NF-ƘB and HIF-1α pathways in non-small cell lung cancer cells.

Abstract

e20049 Background: PD-L1 (programmed death ligand 1) is expressed in various kinds of human tumors including non-small cell lung cancer (NSCLC) and is of critical importance for the immune escape of tumor cells by inhibiting T cell function via its coinhibitory receptor, programmed death 1 (PD-1). Some driver gene mutations including KRAS have been reported to be involved in intrinsic regulation of PD-L1 expression. However, the potential role and precise mechanism of KRAS mutants in regulation of PD-L1 expression in NSCLC cells remain obscure. Methods: We first examined the expression of PD-L1 and key molecules of KRAS signaling pathway in a panel of NSCLC cells with wild-type or mutant KRAS gene. Additionally, KRAS mutant transfection and pharmacological inhibitors of MEK/ERK, PI3K/AKT, and NF-κB were employed to elucidate the regulation mechanism of PD-L1 expression by KRAS mutant in NSCLC cells. We further analyzed KRAS status and protein levels of PD-L1 and hypoxia inducible factor 1 alpha (HIF-1α) in 82 cases of NSCLC tissue. Results: Examination of the KRAS signaling cascades in NSCLC cells revealed an apparent association of PD-L1 overexpression with activation of MEK/ERK and PI3K/AKT pathways. Moreover, NSCLC cells transfected with KRAS mutants and subsequently treated with pharmacological inhibitors showed strong accordance between PD-L1 expression and two transcription factors, NF-κB and HIF-1α. Further transfection or depletion of HIF-1α increased or decreased PD-L1 expression in NSCLC cells accompanied by enhanced or reduced p-IκBα level, respectively, indicating the central role of HIF-1α in upregulating PD-L1 expression in a mechanism parallel to and partially dependent on activation of the NF-κB pathway. Moreover , PD-L1 expression was detected in 31.7% of 82 NSCLC tissues and showed positive correlation with the rate of HIF-1α expression (52.4%). Conclusions: Taken together, KRAS mutants were identified to regulate PD-L1 expression by activating PI3K/AKT and MEK/ERK pathways via NF-κB and HIF-1α, suggesting the correlation between driver gene mutation and tumor immune escape in NSCLC.