eEF2K对三阴性乳腺癌肿瘤免疫的调节作用及机制研究

免疫疗法已成为有效肿瘤治疗手段，三阴性乳腺癌（TNBC）PD-L1高表达，但免疫细胞肿瘤浸润能力低，是免疫治疗效果不佳的主要原因之一。我们发现eEF2K在TNBC中高表达。体内动物实验提示了eEF2K可能通过调控肿瘤微环境中T细胞浸润促进TNBC细胞生长。进一步研究发现eEF2K不仅通过下调Stat1蛋白表达水平，抑制CXCL10转录，影响T细胞肿瘤浸润；也能通过磷酸化GSK3β，抑制PD-L1降解上调其蛋白表达水平，导致免疫逃逸。本项目拟通过细胞和动物模型、临床样本，确定抑制eEF2K上调CXCL10并下调PD-L1，发挥增强T细胞肿瘤浸润和杀伤的双重作用；阐明eEF2K-Stat1-CXCL10和eEF2K-GSK3β-PD-L1的调控机制；证明联合应用eEF2K抑制剂可增强抗PD-1和CTLA4治疗效果。通过该项目为确立eEF2K作为TNBC肿瘤免疫治疗的新靶点提供理论与实验依据。

Immunotherapy has become one of the effective therapies for cancer patients. Triple-negative breast cancer (TNBC) has high PD-L1 expression and low infiltration of immune cells into tumor tissues, leading to unsatisfactory outcome of immunotherapy. We found that eEF2K is highly expressed in TNBC. In vivo experiments indicate that eEF2K may promote TNBC cell proliferation by regulating T cell infiltration into tumor microenvironment. Furthermore, we found that eEF2K not only decreases expression of Stat1 protein, which can inhibit CXCL10 transcription, thereby affecting T cell infiltration into tumor, but also phosphorylates GSK3β, which increases PD-L1 protein expression by inhibiting its degradation, leading to immune escape. In this application, we propose to investigate the role of eEF2K in regulating tumor immunity in TNBC and explore the molecular mechanisms involved, in the hope of establishing the eEF2K-Stat1-CXCL10 and eEF2K-GSK3β-PD-L1 as new signaling pathways in tumor immunity. Our hypothesis is that targeting eEF2K can increase CXCL10 and decrease PD-L1 via those pathways, enhancing the sensitivity of TNBC cells to anti-PD-1 and anti-CTLA4 treatments. The proposed study will reveal eEF2K as a novel therapeutic target for tumor immunity.