葡萄糖转运蛋白3(GLUT3)诱导弥漫大B细胞淋巴瘤化疗耐药的分子机制研究

Resistance of tumor cells to chemotherapy is the main cause of refractory in diffuse large B cell lymphoma (DLBCL) and overcoming chemotherapy resistance remains to be an important problem in the field of DLBCL. The change of tumor metabolic process and microenvironment is recognized to play an important role in cancer progression, but its relationship with DLBCL chemotherapy resistance is not clear. Our previous studies have found that the expression of glucose transporter protein 3 (GLUT3) was increased in the tissues of chemotherapy resistant patients and inhibition of the expression of GLUT3 could significantly improve the drug resistance. The proportion of PD-L1 positive N2 tumor-associated neutrophils increased and T cell function was inhibited in drug resistant tumor microenvironment. The aim of this study is to determine the key factors and main pathways that mediate the GLUT3 based metabolic reprogramming and microenvironmental immunosuppression by a variety of scientific research methods, such as metabolomics, molecular biology, immunology, in vivo, vitro and clinical patient specimen level. This study will reveal the molecular regulatory network of DLBCL chemotherapy resistance, which provided theoretical basis and potential drug target for reversing DLBCL chemotherapy resistance.

肿瘤细胞对化疗药物耐药是临床上弥漫大B细胞淋巴瘤（DLBCL）难治的主要原因，是研究领域亟待解决的重要问题。肿瘤本身代谢和微环境的改变在其发生发展中起到重要的调控作用，但其与DLBCL化疗耐药是否有联系尚无相关研究。本课题前期结果发现葡萄糖转运蛋白3（GLUT3）在化疗耐药患者组织中表达增加，抑制其表达可以显著改善耐药；耐药肿瘤微环境中PD-L1阳性N2型肿瘤相关中性粒细胞比例增加，T细胞功能受抑制。本课题拟从体内、体外、临床患者标本水平，利用代谢组学、分子生物学、免疫学等多种科学研究方法，重点研究GLUT3启动的代谢重塑作用及其诱导的免疫抑制微环境调控DLBCL化疗耐药的分子机制，从多角度入手，揭示DLBCL化疗耐药的分子调控网络，为临床逆转DLBCL化疗耐药提供理论依据和潜在的药物作用靶点。

弥漫大B细胞淋巴瘤（DLBCL）肿瘤本身代谢和微环境的改变在耐药中起到重要的调控作用。本课题通过临床患者组织标本、细胞实验、动物实验证实了高表达葡萄糖转运蛋白3（GLUT3）蛋白的DLBCL细胞糖酵解速率增强，肿瘤生长快，对化疗药物耐药。高表达GLUT3的细胞在乳酸环境下通过GM-CSF调控肿瘤相关中性粒细胞分化成PD-L1+中性粒细胞。同时高表达GLUT3的细胞抑制CD8+T细胞的增值和功能。揭示了GLUT3启动的代谢重塑作用及其诱导的免疫抑制微环境（中性粒细胞、T细胞）调控DLBCL化疗耐药的分子机制，这些研究工作阐明了GLUT3在DLBCL化疗耐药中的作用，明确了GLUT3诱导DLBCL化疗耐药的机制，为以GLUT3为基础的肿瘤细胞靶向治疗提供理论依据和实验基础。