EGFR通过激活β-catenin重塑肿瘤微环境代谢调控肿瘤免疫逃逸的分子机制研究

EGFR激活对肿瘤免疫逃逸至关重要，但作用机制尚不清楚。胞膜CD73水解胞外AMP产生的腺苷来抑制细胞毒性T细胞促进肿瘤免疫逃逸，EGFR是否参与CD73的表达调控未知。我们前期实验结果显示，EGFR激活的β-catenin上调肿瘤细胞Lnc1574203和CD73的表达。据此，我们提出假说：EGFR通过β-catenin诱导Lnc1574203表达，上调的Lnc1574203促进CD73表达继而腺苷生成，导致细胞毒性T细胞抑制和肿瘤免疫逃逸。本课题将（1）揭示β-catenin上调Lnc1574203的机制；（2）阐明Lnc1574203促进CD73表达及抑制细胞毒性T细胞功能；（3）探讨阻断EGFR/β-catenin/Lnc1574203/CD73信号传导增强PD-1抗体免疫治疗的效果。该研究将阐明EGFR激活促进肿瘤免疫逃逸的重要机制，为发展新的肿瘤治疗方法提供理论依据。

EGFR activation is critical for tumor immune evasion. However, the mechanism underlying EGFR activation-regulated tumor immune evasion is unclear. The adenosine produced by membrane CD73 via hydrolyzing extracellular AMP is essential for inhibited cytotoxic T cell function and subsequent tumor immune evasion. However, the mechanism underlying EGFR activation-regulated CD73 expression is elusive. Preliminary results revealed that EGFR-induced β-catenin transactivation upregulated the expression levels of Lnc1574203 and CD73 in tumor cells. Therefore, we come up with a hypothesis that EGFR-induced β-catenin transactivation promotes Lnc1574203 expression. The upregulated Lnc1574203 enhances CD73 expression and adenosine production, leading to cytotoxic T cell function inhibition and tumor immune evasion. In the proposed studies, we will (1) determine the mechanism underlying β-catenin-upregulated Lnc1574203 expression; (2) decipher the mechanism underlying Lnc1574203-upregulated CD73 expression and Lnc1574203-inhibited cytotoxic T cell function; (3) investigate the effect of blocked EGFR/β-catenin/Lnc1574203/CD73 signaling on enhanced anti-PD-1 immunotherapy. This project will decipher the vital mechanism underlying EGFR activation-elicited tumor immune evasion, and provide new strategies and rationales for clinical treatment of human cancers.