ArticleFrontiers in oncology2025
Suppression of NK cell-mediated immunosurveillance by IL-35 drives tumor progression in EGFR-mutant non-small cell lung cancer.
Article in Frontiers in oncology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Background: Interleukin-35 (IL-35) is an added member of the IL-12 heterodimeric cytokine family, composed of two subunits: EBI3 and P35 subunits, implicated in tumor immune evasion. This study investigates the expression and immunosuppressive role of IL-35 in epidermal growth factor receptor (EGFR)-mutant non-small cell lung carcinoma (NSCLC), with a focus on its interaction with natural killer (NK) cells. Methods: Eighty-two NSCLC tissue samples (47 EGFR-mutant and 35 wild-type) were assessed for IL-35 expression via immunohistochemistry (IHC) targeting EBI3 and P35. ELISA, Western blot, and PCR validated protein and mRNA expression in fresh tissues (n = 14). The degree of NK-cell infiltration was evaluated as the percentage of NKp46-positive cells among CD45-positive cells. Peripheral NK cells were isolated from healthy donors and subjected to IL-35 treatment. Functional assays included CCK8, flow cytometry for CD3-CD56+ cells and NKG2D, ELISA for cytokine secretion, and cytotoxicity assays on NSCLC cell lines. Results: IL-35 was significantly overexpressed in EGFR-mutant NSCLC tissues, with strong concordance between EBI3 and P35(r = 0.795, P < 0.0001). High IL-35 expressions associated with larger tumor size (χ2 = 16.140, P = 0.000) and EGFR mutation status (χ2 = 4.843, P = 0.028). IL-35 expression levels were associated with patient prognosis in both the overall population and the EGFR-mutant subgroup (Kaplan-Meier, P < 0.05).IL-35 expression inversely correlated with NKp46- cell density (r = -0.526, P = 0.000). The percentage of NKp46-positive cells among CD45-positive cells differed significantly between mutant and wild-type NSCLC tissues (t=-9.083,P=0.000). IL-35 inhibited NK cell proliferation and function Conclusion: IL-35 is upregulated in EGFR-mutant NSCLC and mediates immune suppression by impairing NK cell activity. Targeting IL-35 may offer a therapeutic avenue to restore NK cell function and enhance anti-tumor immunity.
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