CD28缺失导致CTL衰老与淋巴瘤抵抗PD-1单抗的相关性及机制研究

近年来PD-1单抗已经应用于淋巴瘤的临床治疗，然而PD-1单抗抵抗的机制不完全清楚。我们曾报道了阻断PD-1可以部分恢复T细胞的免疫功能，同时在此研究中我们发现PD-1单抗作用的靶细胞中存在CD28-CD57+细胞亚群，这一亚群细胞以免疫衰老为特征。进一步分析提示CD28-CD57+亚群与淋巴瘤预后呈负相关，且与血清IL-8和IL-27水平呈正相关，提示CD28-CD57+亚群是参与淋巴瘤免疫反应的重要细胞。综上我们假设CD28-CD57+亚群参与PD-1单抗抵抗。在本项目中，基于CD28和CD57的表达分选淋巴瘤患者PD-1阳性T细胞的不同亚群，对比分析免疫耗竭和衰老的表型特点、基因表达特点、抗肿瘤免疫功能和对PD-1单抗的反应；应用体外实验和小鼠模型探索CD28-CD57+亚群参与PD-1单抗抵抗的机制，从而为PD-1单抗抵抗提供了机制性研究，并为PD-1单抗抵抗提供了临床解决方案。

Treatment targeting immune checkpoint PD-1 has been demonstrated to be safe and efficacious in lymphoma, but the mechanism of resistance to PD-1 blockade is still unclear. We have reported previously that PD-1 was highly expressed in lymphoma, and the immune response could be partially recovered by PD-1 blockade. Meanwhile, we found a subgroup of cells in PD-1 positive cell population characterized by CD28-CD57+. Some studies have proven that CD28-CD57+ represented senescence of T cells. Based on the expression of CD28 and CD57 in PD-1+ T cell population, we plan to identify the T-cell subsets to distinguish PD-1 resistant T-cells. In this program, we intend to sort different T-cell subsets in PD-1 positive cells and confirm the distinction between CD28-CD57+ and CD28+CD57+ cells in immune exhaustion, aging phenotype, the expression of senescence associated gene, anti-tumor immune function and the effectiveness to PD-1 monoclonal antibody, furthermore, we am gonging to investigate the mechanism of PD-1 resistance and find out how to reverse the PD-1 resistance caused by T-cell senescence. Our research provides a feasible method to overcome PD-1 resistance.