PD-1及配体PD-L1/2是T细胞活化过程中重要的负性共刺激分子，与肿瘤免疫耐受和逃逸密切相关，阻断PD-1及配体的靶向药物是目前肿瘤免疫治疗的研究热点之一。我们在前期研究中发现：PD-L2在结直肠癌细胞和组织中阳性表达率高于PD-L1；K-Ras突变细胞中PD-L2蛋白水平高于野生型，抑制PD-L2可以增加K-Ras突变细胞对TRAIL诱导凋亡的敏感性。据此我们提出假说"PD-1/PD-L2介导的免疫抑制可能是K-Ras突变结直肠癌免疫逃逸的重要机制"。本项目将研究PD-L2与K-Ras突变结直肠癌临床病理及预后的关系，揭示PD-L2/PD-1在以CD8+为主的抗肿瘤免疫中的作用，阐明PD-L2表达是否对K-Ras突变存在依赖性及分子机制。研究结果将明确K-Ras突变调控结直肠癌中PD-L2表达并促进肿瘤细胞免疫逃逸作用和分子机制，为该类型肿瘤靶向免疫治疗提供坚实的理论基础。

Programmed death 1 (PD-1) protein, a T-cell coinhibitory receptor, and its ligands, PD-L1 and PD-L2, play a pivotal role in the ability of tumor cells to evade the host's immune system. Blockade of interactions between PD-1 and PD-L1 enhances immune function in vitro and mediates antitumor activity in preclinical models. Our preliminary studies suggest that 1)In colorectal cancer tissue and cell lines, the positive rate of PD-L2 is higher than that of PD-Ll;2) The protein expression is higher in K-Ras mutant cells than in K-Ras wild type cells; 3) Down-regulation of PD-L2 can sensitize K-Ras mutant cells to the TRAIL indused apoptosis. All these data suggest that the PD-L2 plays an important role in immune suppression of colorectal cancer. Here we hypothesize that up-regulation of PD-L2 pathway may contribute to the immune escape of K-Ras-driven colorectal tumor. The aims of this study are: 1.to explore the relationship between PD-L2 expression and the pathologic diagnosis and prognosis of the colorectal cancer; 2.to understand if blockade of PD-L2/PD-1 pathway could effectely restore the CD8+ T cell function in tumor; 3.to identify the correlation ship between K-Ras mutation and the immunosuppression manifected by PD-L2 upregulation in colorectal cancer. In summary, a better understanding of PD-L2 will provide a novel insight into the mechanisms of immune escape associated K-Ras mutation and in the end may serve to shift paradigms relating to Ras signaling and immunotherapy.