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

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Programmed cell death protein-1 (PD-1) and ligand (PD-L1) checkpoint blockade shows promise in non-small-cell lung cancer (NSCLC).
• Identifying patient subtypes responsive to immunotherapy remains a challenge.
• Mutant Kirsten rat sarcoma viral oncogene homolog (KRAS) is common in NSCLC, associated with poor prognosis.

Purpose of the Study:

• To investigate the relationship between mutant KRAS and PD-L1 expression in NSCLC.
• To elucidate the mechanism by which KRAS influences PD-L1.
• To evaluate the efficacy of PD-1 blockade in KRAS-mutant NSCLC.

Main Methods:

• Analysis of PD-L1 levels in KRAS-mutant NSCLC cell lines and patient tissues.
• Overexpression and suppression of KRAS G12V in cell lines.
• In vitro and in vivo assays using tumor xenografts in mice.
• Assessment of pembrolizumab's effect on tumor growth and antitumor activity.

Main Results:

• KRAS mutant cell lines, particularly those with KRAS G12V, exhibited significantly increased PD-L1 mRNA and protein levels.
• KRAS G12V overexpression upregulated PD-L1, while its suppression decreased PD-L1 levels.
• Higher PD-L1 expression was observed in KRAS-mutated tissues and associated T cells.
• KRAS G12V upregulated PD-L1 via the transforming growth factor-β/epithelial-to-mesenchymal transition (EMT) pathway.
• Pembrolizumab demonstrated antitumor activity and reduced tumor growth in KRAS G12V-mutant NSCLC models.

Conclusions:

• KRAS G12V mutation induces PD-L1 expression and promotes immune escape in NSCLC through the TGF-β/EMT pathway.
• This finding identifies a potential therapeutic strategy for NSCLC patients with KRAS mutations.
• Targeting PD-1/PD-L1 signaling offers a promising approach for KRAS-mutant NSCLC immunotherapy.