KRAS G12V mutation upregulates PD‐L1 expression via TGF‐β/EMT signaling pathway in human non‐small‐cell lung cancer

Abstract Although clinical data suggest remarkable promise for targeting programmed cell death protein‐1 (PD‐1) and ligand (PD‐L1) signaling in non‐small‐cell lung cancer (NSCLC), it is still largely undetermined which subtype of patients will be responsive to checkpoint blockade. In the present study, we explored whether PD‐L1 was regulated by mutant Kirsten rat sarcoma viral oncogene homolog (KRAS), which is frequently mutated in NSCLC and results in poor prognosis and low survival rates. We verified that PD‐L1 levels were dramatically increased in KRAS mutant cell lines, particularly in NCI‐H441 cells with KRAS G12V mutation. Overexpression of KRAS G12V remarkably elevated PD‐L1 messenger RNA and protein levels, while suppression of KRAS G12V led to decreased PD‐L1 levels in NCI‐H441 cells. Consistently, higher levels of PD‐L1 were observed in KRAS‐mutated tissues as well as tumor tissues‐derived CD4 + and CD8 + T cells using a tumor xenograft in B‐NDG mice. Mechanically, both in vitro and in vivo assays found that KRAS G12V upregulated PD‐L1 via regulating the progression of epithelial‐to‐mesenchymal transition (EMT). Moreover, pembrolizumab activated the antitumor activity and decreased tumor growth with KRAS G12V mutated NSCLC. This study demonstrates that KRAS G12V mutation could induce PD‐L1 expression and promote immune escape via transforming growth factor‐β/EMT signaling pathway in KRAS‐mutant NSCLC, providing a potential therapeutic approach for NSCLC harboring KRAS mutations.