化疗药物介导淋巴瘤微环境代谢变化对T细胞免疫功能的影响及其干预策略

Chemotherapy is an important strategy of lymphoma treatment. However, many patients relapse because of the impaired immunity after the chemotherapy. Many studies show that lymphocytes can be killed directly by chemo-agents, but there is little research focus on the immune regulation effects by metabolism regulation of microenvironment. In the previous study, we found that doxorubicin induced a rise of glycolytic capacity and the production of lactate in lymphoma and stroma cells, which affect the glucose concentration and PH in microenvironment. Furthermore, we found that if CD4 T or CD8 T lymphocytes con-culture with the lymphoma cells, the proliferation of T lymphocytes are inhibited significantly. Therefore, the mechanism of impaired immunity can be not only the directly effects of the chemotherapy drugs but the metabolic changes of microenvironment. However rare study focuses on the mechanism of the modulation of T lymphocytes by microenvironment metabolism changes. In the present study, we plan to further investigate the mechanism of doxorubicin induced metabolic changes in lymphoma and stroma cells and how microenvironment regulates the function of T lymphocytes. The tumor growth inhibition effects of inhibitors of glycolytic combined with immunotherapy were also study, using mouse model in vivo. This study will provide foundation in treating lymphoma by anti-metabolic agent combined with chemotherapy.

化疗是淋巴瘤治疗的重要手段，但淋巴瘤患者化疗后常出现免疫功能下降引起复发。目前认为化疗药物可直接杀伤淋巴细胞，但对微环境代谢变化调节免疫功能的研究较少。我们前期研究发现，阿霉素可引起淋巴瘤及基质细胞糖酵解活性及产乳酸量升高，从而改变微环境中葡萄糖浓度及酸碱度。进一步实验发现，阿霉素处理后的淋巴瘤细胞与CD4、CD8T淋巴细胞共培养，淋巴细胞增殖受到明显抑制。因此，化疗药物引起淋巴瘤患者T淋巴细胞免疫功能下降，可能是通过对淋巴瘤微环境代谢改造而引起的，但目前对该过程的具体发生机制仍不明确。故本项目中，我们拟深入研究ADM调节淋巴瘤、基质细胞代谢机制，同时通过共培养模型，研究淋巴瘤微环境代谢变化对T淋巴细胞免疫功能的影响及其与T淋巴细胞代谢变化的关系。并行小鼠体内实验，评价化疗联合抗代谢药物治疗的疗效，并研究体内T淋巴细胞免疫功能及代谢变化。本研究将为化疗联合抗代谢药物治疗淋巴瘤提供理论基础。

化疗是淋巴瘤治疗的重要手段，但淋巴瘤患者化疗后常出现免疫功能下降引起复发。目前化疗药物对微环境代谢变化调节及基质细胞PDL1表达及其对免疫功能的影响研究较少。本研究发现低浓度化疗药物对可明显诱导基质细胞PDL1表达升高，并且基质细胞PDL1表达升高主要依赖于产生细胞因子GM-CSF以促使细胞内ERK1/2的磷酸化以激活ERK1/2信号转到通路。同时在淋巴瘤患者原代骨髓基质细胞及小鼠体内实验得到证实。更重要的是，探索了化疗药物诱导基质细胞PDL1表达升高对CD8 T淋巴细胞凋亡及分泌功能的影响，同时联合使用PDL1抗体可逆转此种对CD8 T淋巴细胞功能的不利影响。总之，本研究为淋巴瘤患者经单独化疗后复发的原因提供了新的解释，为临床中化疗联合PD1/PDL1抗体治疗淋巴瘤提供了一定的理论基础，该联合治疗方案值得在临床经临床研究后在临床中推广。