TP63抑制食管癌中CD8+T细胞浸润/活化的分子机制研究

抑制CD8+T细胞浸润和活化是肿瘤免疫逃逸的重要机制。我们前期研究发现，TP63高表达的食管癌组织中CD8+T细胞浸润和活化程度较低。TP63是食管癌特异的转录因子，维持食管癌细胞自身的多种恶性表型。目前尚不清楚TP63如何抑制CD8+T细胞的浸润和活化。我们进一步的小鼠体内外预实验结果显示，沉默TP63会增加CD8+T细胞的浸润程度和杀伤能力。分子机制上，TP63和干扰素γ信号通路重要转录因子STAT1存在竞争性调节关系，沉默TP63能激活干扰素γ信号通路相关基因的表达。因此我们推测TP63可能通过抑制干扰素γ通路影响CD8+T细胞浸润和活化，诱导癌细胞发生免疫逃逸。本项目拟在前期工作基础上，利用体内体外实验深入研究TP63如何影响CD8+T细胞浸润和活化，并详细揭示其内在分子机制，为食管癌的免疫治疗提供更多的理论依据和治疗策略。

Suppression of CD8+T cell infiltration and activation confers immune evasion of tumor cells. Our recently findings observed that overexpression of TP63 in esophageal squamous cell carcinoma (ESCC) tumor with low infiltration and activation of CD8+T cells. TP63 is a master transcription factor, playing a vital role in the maintenance of various malignant phenotypes in ESCC. However, the mechanism underlying TP63 suppressed CD8+T cell infiltration and activation has yet appreciated. Our preliminary data has shown that downregulation of TP63 induced more infiltration and activation of CD8+T cells, and led to the further effective cancer cell killing relative to control in syngeneic xenograft mice models and ex vivo co-culture system. Further investigation of the molecular mechanisms indicated a reciprocal inhibition between TP63 and STAT1, the important transducers and activators of interferon-γ (IFN γ) pathway, by competitively occupying IFN γ response genes. In addition, the expression of some IFN γ response genes were markedly increased after silencing of TP63 in ESCC. Therefore, we hypothesize that hyperactivation of TP63 impacts CD8+T cells infiltration and activation in ESCC by suppressing IFN γ signaling pathway and consequently facilitates immune evasion. Based on our previous data, this study will decipher the detailed mechanism by which TP63 affects CD8+T cells infiltration and activation. Our findings will advance the understanding of the tumor microenvironment and immune evasion of ESCC, facilitate development of novel biomarkers and therapeutic targets for immunotherapy of this aggressive malignancy.