Unique Pathways that drive CD8+ T cell dysfunction and immune evasion in lung adenocarcinoma

Abstract WNT ligands have been critically implicated in many aspects of lung cancer progression. This study explores the impacts of Wnt family member 10A (WNT10A) in progression and immune response in lung adenocarcinoma (LUAD) and investigates the underpinning mechanisms. Expression, prognosis, and immune correlations of WNT10A in LUAD were explored using TCGA-LUAD, GEO datasets, and tissue microarrays. In vitro, WNT10A was knocked down in LUAD cell lines (H441 and H1299), followed by RNA sequencing and functional assays. Tumor-bearing mouse models with WNT10A knockdown were used to assess tumor growth and immune response. The functions of WNT10A on CD8 + T cell cytotoxicity were further explored through co-culture experiments and flow cytometry. FRAT1 overexpression, Wnt activators (BML-284), and CXCL12 manipulations were employed to verify mechanistic links. High WNT10A expression showed a trend toward poor overall survival, reduced CD8 + T cell infiltration, and unfavorable prognosis in LUAD patients. WNT10A loss in LUAD cells reduced growth, mobility, and inhibited Wnt signaling. In vivo, WNT10A loss prolonged animal survival in immunocompetent mice, reduced tumorigenic activity of mouse 3LL cells, and enhanced CD8 + T cell activity and tumor cell apoptosis. Mechanistically, WNT10A promoted FRAT1-mediated suppression of GSK3β, facilitating CTNNB1 activation and CXCL12 expression, which restricted CD8 + T cell function. WNT10A silencing synergized with anti-PD-1, reducing tumor burden and boosting CD8 + T cell infiltration/function. Generally, WNT10A promotes LUAD progression and CD8 + T cell dysfunction through FRAT1-mediated Wnt signaling and CXCL12 activation. Focusing on WNT10A could offer a compelling approach to boosting T cell-driven anti-tumor responses for the treatment of LUAD.