Role of the Wnt5A pathway in resistance to immune checkpoint inhibitors in advanced Non-Small Cell Lung Cancer

β-catenin-independent Wnt signaling plays a role in lung carcinogenesis, but its impact on prognosis and immune response in Non-Small Cell Lung Cancer (NSCLC) patients receiving immune checkpoint inhibitors (ICI) remains unclear. This study evaluates the prognostic significance of Wnt5a and Wnt5b and their role in immune modulation.

A prospective cohort of 52 consecutive advanced NSCLC patients receiving first-line ICI therapy was analyzed. Plasma samples were analysed using ELISA to quantify Wnt5a/Wnt5b. PBMCs were stimulated with PHA ± Pembrolizumab and co-cultured with recombinant Wnt5a or NSCLC explants. Wnt signaling inhibition was achieved using porcupine inhibitors (IWP-2/IWP-4) or neutralizing Wnt5a antibody. CD8 + T cell activation and cytokine production (INFγ, IL-6, IL-10) were measured by flow cytometry and ELISA.

We observed that Wnt5a levels were significantly elevated in NSCLC patients and correlated with poor tumor response (RR = 2.4, p = 0.05) and shorter progression-free survival (Hazard Ratio (HR) = 2.77; 95% CI 1.11-6.88; p = 0.028.). In vitro, Wnt5a suppressed CD8 + T cell activation and INFγ production. These immunosuppressive effects were reversed by Wnt5a inhibitors, highlighting their potential as therapeutic agents to improve immune response in NSCLC patients receiving ICI therapy.

Overall, high Wnt5a correlates with immune suppression and poor ICI response, suggesting its potential as a predictive biomarker and therapeutic target in NSCLC.