Abstract 203: TCF12 regulates PD-L1 expression through TGF-beta signaling and modulates the immune microenvironment in micropapillary lung cancer

Abstract Background: The prognosis of lung adenocarcinoma (LUAD) is strongly influenced by its histologic growth patterns, with the micropapillary component (MPC) being a poor prognostic indicator. However, the molecular mechanisms driving the poor prognosis of the MP subtype remain unclear, particularly regarding spatial transcriptomic (ST) insights. Methods: Spatial transcriptomics (10X Genomics) was performed on 4 LUAD cases to map gene expression. Targeted next-generation sequencing (NGS) on 72 LUAD samples evaluated genetic alterations. The roles of TCF12 and its regulation via the TGF-β pathway were explored through in vitro and in vivo studies, including CCK-8 assays for cell proliferation, Transwell migration and invasion assays, and sphere formation assays to assess tumorigenic potential. Western blotting and PCR were used to analyze protein and gene expression levels, respectively. Immunohistochemistry of 160 LUAD samples validated TCF12 and PD-L1 expression correlations. Furthermore, mouse xenograft tumor models were employed to verify the effects of TCF12 on tumor growth and its interaction with the TGF-β pathway and PD-L1 expression in vivo. Results: The first spatial transcriptomic map of LUAD revealed significant spatial heterogeneity, with the MP pattern strongly linked to TGF-β signaling and immune responses. TCF12 was highly expressed in MP regions, activating TGF-β signaling and upregulating PD-L1 expression. Functional assays demonstrated that TCF12 overexpression promoted proliferation, invasion, and angiogenesis in LUAD, which were suppressed by TGF-βRI kinase inhibition. In animal models, dual inhibition of TGF-β and PD-L1 significantly reduced tumor growth in TCF12-overexpressing tumors compared to single-drug and control groups. Immunohistochemistry showed that increased TCF12 expression correlated with poor survival, lymph node metastasis, and MP pattern presence. Conclusions: TCF12 drives PD-L1 expression via TGF-β signaling, fostering an immunosuppressive microenvironment in LUAD. Dual inhibition of TGF-β and PD-L1 restores immune function, offering a promising strategy for MP-LUAD precision therapy. Keywords: TCF12, Spatial transcriptomics, TGF-β signaling, PD-L1, Lung adenocarcinoma, Micropapillary component Citation Format: Yifei Liu, Ting Wang, Tingting Bian, Jia Feng, Qiushi Lin, Xiaoqun Dong. TCF12 regulates PD-L1 expression through TGF-beta signaling and modulates the immune microenvironment in micropapillary lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 203.