Mesenchymal stem cells promote cisplatin resistance in non-small cell lung cancer through IL-6/MEK-ERK/macrophages axis: construction of prognostic signature and experimental investigation.

[BACKGROUND] Cisplatin is a primary treatment for non-small cell lung cancer (NSCLC), however, cisplatin resistance develops readily, leading to tumor progression. Mesenchymal stem cells (MSCs) distributed in the tumor microenvironment (TME), yet the effects and mechanisms of cisplatin on MSCs and their subsequent impact on TME remains unclear.

[METHODS] The MSC-related prognostic signature was developed through Cox and LASSO regression analysis. Validation was performed by survival analysis, ROC analysis and nomogram construction. TME evaluation was carried out by GSEA and immune infiltration analysis. The effect of cisplatin on MSCs was investigated by polymerase chain reaction (PCR) array, qRT-PCR, ELISA and Western blot. The migration of RAW 264.7 macrophages was analyzed by transwell assays and the polarization was analyzed by flow cytometry.

[RESULTS] High-risk of MSC-related prognostic signature (PDGFB, ANPEP, CD40) was significantly linked to poor prognosis in patients under cisplatin treatment for NSCLC and other cancers. Patients with high IL-6 expression demonstrated poor response to cisplatin therapy. MSCs were linked with an immunosuppressive TME characterized by macrophage infiltration, particularly M2 macrophages. Cisplatin upregulated IL-6 expression in MSCs via the MEK-ERK pathway. The ability of MSCs to promote RAW 264.7 macrophages recruitment and polarization was enhanced by cisplatin.

[CONCLUSION] We established MSC-related prognostic signature for cisplatin therapy in NSCLC. MSCs and IL-6 were associated with cisplatin resistance and macrophages infiltration. Thus, MSCs and IL-6 were potential targets for NSCLC therapeutic intervention.