弥漫大B细胞淋巴瘤微环境PTEN缺失在介导CD8T细胞耗竭中的作用机制及临床意义

弥漫大B细胞淋巴瘤(DLBCL)微环境中是否存在CD8T细胞耗竭的分子调控机制及临床意义目前未见研究报道。前期研究我们发现相比正常组织，DLBCL组织中浸润富集大量的CD8T细胞；但其免疫抑制性受体PD-1,TIGIT,LAG3均显著性高表达；提示在DLBCL肿瘤微环境中CD8T细胞功能可能处于耗竭状态；但其分子调控机制尚不明确。基于我们前期研究发现：相比正常组织DLBCL存在PTEN基因缺失，且PTEN负调控DKK3表达，提示PTEN缺失能够抑制WNT/β-Catenin信号通路；由此我们提出科学假设：DLBCL中PTEN缺失，上调DKK3表达，从而抑制WNT/β-Catenin信号通路，进而募集CD8T细胞浸润参与T细胞耗竭。本项目拟从临床组织标本，体外细胞培养和体内动物模型三个层次探讨PTEN基因缺失在介导DLBCL肿瘤微环境T细胞耗竭中的作用及调控机制，为临床治疗提供新的靶点。

There is no research report on the molecular regulatory mechanism and clinical significance of CD8T cell depletion in the microenvironment of diffuse large B-cell lymphoma (DLBCL). In previous studies, we found that compared with normal tissues, DLBCL tissues were infiltrated and enriched with a large number of CD8T cells; however, their immunosuppressive receptors PD-1, TIGIT, and LAG3 were significantly overexpressed; suggesting that in DLBCL tumor microenvironment CD8T cells may be in a state of exhaustion; but its molecular regulatory mechanism is not yet clear. Based on our previous research, we found that compared with normal tissues, there was PTEN gene deletion in DLBCL, and PTEN negatively regulates DKK3 expression, suggesting that PTEN deletion can inhibit the WNT / β-Catenin signaling pathway; thus we propose a scientific hypothesis: PTEN deletion in DLBCL, up-regulation of DKK3 expression, thereby inhibiting the WNT / β-Catenin signaling pathway, and then recruiting CD8 T cell infiltration to participate in T cell exhaustion. This project intends to explore the role and regulatory mechanism of PTEN gene deletion in mediating DLBCL tumor microenvironment T cell exhaustion from three levels: clinical tissue specimens, in vitro cell culture and in vivo animal models, to provide new therapeutic targets for clinical treatment.