PD-1/PD-L1通路介导手术创伤后T淋巴细胞功能障碍的机制研究

The PD-1/PD-L1 pathway has been proved to be involved in tumor-induced cellular immunosuppression and septic cellular immunosuppression. However, it is still unclear whether the pathway is involved in the surgery-induced dysfunction of T lymphocytes. Our preliminary experiments indicated increased serum level of IL-2 and IFN-a, and significant up-regulation of PD-1 on T lymphocytes and its ligand PD-L1 on monocytes from peripheral blood after pulmonary lobectomy. In addition, the caspase-3 expression on T lymphocytes increased after sugery, and their cells count decreased. Anti-PD-1 antibody can reverse the partial liver resection-induced shorter survival time of mice with lung cancer. It suggested that the pathway may be involved in the surgery-induced dysfunction of T lymphocytes, but its potential mechanism needs to be further investigated. We propose the following hypothesis: Surgery-induced inflammation and stress incrased the serum level of induced IL-2 and IFN-a, and then induced the up-regulation of PD-1 on T lymphocytes, which resulted in the Th1/Th2 imbalance, decreased the IFN-γ secretion and proliferation of T lymphocytes, and then promoted the apoptosis of T lymphocytes. The above alterations inhibited the possible immune destruction aiming at the minimal residunal tumor cells and shedding tumor cells during surgery,and then increased the tumor metastasis and recurrence. Blocking this pathway would reverse the dysfunction of T lymphocytes, then alleviate the trauma-induced immune suppresion, and finally improve the prognosis of patients with cancer. To test our hypothesis, we will use patients receiving pulmonary lobectomy and PD-1 gene knockout mice to investigate the role of the PD-1/PD-L1 pathway in perioperative cellular immune suppression from molecules, cell, animal and clinical prognosis, in order to provide a new idea for prevention postoperative immune suppression.

PD-1/PD-L1通路诱导了肿瘤性和脓毒性细胞免疫抑制，那么它是否介导了手术创伤后T细胞功能抑制呢？迄今尚无相关报道。我们的前期实验提示：肺叶切除术后血浆IL-2、IFN-a水平增加，外周血T细胞PD-1、单核细胞PD-L1表达上调，且T细胞凋亡加速、细胞数减少；手术创伤可缩短肺癌小鼠生存期且该效应可被抗PD-1抗体逆转。这提示，该通路介导了手术创伤后的T细胞功能抑制，但其机制有待深入探讨。为此，我们提出以下假设：手术后的创伤应激提升了血浆IL-2、IFN-a水平，上调了T细胞PD-1的表达，促使Th1/Th2失衡，引起T细胞功能减退并加速凋亡，使得术中残留或脱落的肿瘤细胞易于逃脱免疫杀伤，进而发生转移和复发，而阻断该通路可逆转T细胞功能障碍，改善肿瘤预后。本课题将从分子、细胞、动物以及临床预后等方面探讨PD-1/PD-L1通路在术后T细胞功能抑制中的作用，为防治术后免疫抑制提供新思路。