c-MET/NF-κB axis modulates PD-L1 and CCL22-mediated immune evasion and its inhibition enhances anti-PD-1 efficacy in non-small cell lung cancer.

Background

c-MET overexpression is common in non-small cell lung cancer (NSCLC) and associated with poor prognosis, however, its role in immune evasion and immunotherapy resistance remains unclear.

Methods

We analyzed c-MET expression in public "The Cancer Genome Atlas NSCLC" cohort (n = 1043) and an institutional cohort of 117 NSCLC patients, including 57 advanced cases receiving first-line immunochemotherapy. c-MET expression was assessed via immunohistochemistry and correlated with clinical outcomes and immune markers. Mechanistic studies used c-MET knockdown/overexpression in H1993 and LLC cells, combined with RNA-seq, western blotting, immunofluorescence, and flow cytometry. The in vivo efficacy of capmatinib plus anti-PD-1 antibodies was evaluated using a syngeneic mouse model.

Results

c-MET overexpression was associated with shorter overall and progression-free survival in patients receiving immunochemotherapy and emerged as a potential prognostic factor in this exploratory cohort. c-MET-high tumors exhibited increased PD-L1 expression, reduced CD8+ T cell infiltration, and enrichment of immunosuppressive populations. Mechanistically, c-MET engaged the NF-κB pathway, consistent with coordinated upregulation of PD-L1 and CCL22, as supported by both NF-κB inhibition and agonist rescue. In vivo, c-MET overexpression promoted tumor growth and altered tumor immune cell composition. Combined MET inhibition (capmatinib) and PD-1 blockade synergistically suppressed tumor growth, increased CD8+ T and NK cell infiltration, and reduced regulatory T cells, M2 macrophages, and myeloid-derived suppressor cells; no overt toxicity was noted.

Conclusion

c-MET overexpression promotes immune evasion in NSCLC, potentially through NF-κB-mediated upregulation of PD-L1 and CCL22. Combined MET inhibition and immune checkpoint blockade represents a promising strategy for this patient subset.