三阴性乳腺癌细胞通过谷氨酸促进免疫检查点VTCN1表达的作用及机制研究

三阴性乳腺癌（TNBC）由于缺乏有效靶点，治疗效果不理想。靶向代谢重编程和免疫检查点是肿瘤治疗的新策略。我们前期通过生物信息学和实验研究发现：1）TNBC细胞内可出现谷氨酸累积并外排增多；2）TNBC样本中谷氨酸受体mGluR6表达升高，且与免疫反应负相关；3）在CD8+T细胞富集的乳腺癌样本中，mGluR6高表达患者预后差；4）VTCN1是TNBC最主要的免疫检查点分子，其在TNBC中表达升高，且与mGluR6正相关。由此，我们推测TNBC细胞外排大量谷氨酸并通过mGluR6促进免疫检查点VTCN1的表达，进而抑制CD8+T细胞的功能，实现免疫逃逸。我们将利用体内外模型及临床样本，研究TNBC细胞通过谷氨酸对免疫检查点VTCN1及CD8+T细胞的作用，并进一步探讨谷氨酸调控VTCN1表达的分子机制。本项目的实施将为探索三阴性乳腺癌新的免疫治疗靶点提供科学依据。

Patients with triple-negative breast cancer (TNBC) have poor clinical outcome, as lack of effective targets. Targeting metabolic reprogramming and immune checkpoints have been a novel therapeutic strategy for cancers. We have previously revealed: i) intracellular glutamate is accumulated and excess glutamate is excreted in TNBC cells; ii) glutamate receptor mGluR6 is highly expressed in TNBC and it is negatively correlated with immune response. Poor prognosis of TNBC patients with high CD8+ T cell infiltration is associated with the high expression of mGluR6; and iii) VTCN1 is the most abundant immune checkpoint molecule in TNBC, while its expression has been shown to be positively correlated with mGluR6. Therefore, we hypothesize that the glutamate-mediated activation of mGluR6 signaling in TNBC cells promotes the expression of VTCN1 for suppressing anti-tumor immunity. This project would provide novel targets and scientific basis for the metabolic reprogramming-mediated immune therapy of triple-negative breast cancer.