Cancer immunology, immunotherapy : CII · 2026
Role of the Wnt5A pathway in resistance to immune checkpoint inhibitors in advanced Non-Small Cell Lung Cancer.
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Takam Kamga Paul, Costantini Adrien, Capron Claude, Glorion Mathieu, Julie Catherine, Emile Jean-François, Giroux-Leprieur Étienne
Аннотация
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: Overall, high Wnt5a correlates with immune suppression and poor ICI response, suggesting its potential as a predictive biomarker and therapeutic target in NSCLC.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: Overall, high Wnt5a correlates with immune suppression and poor ICI response, suggesting its potential as a predictive biomarker and therapeutic target in NSCLC.