胃癌组织中巨噬细胞调控CD103阳性组织固有T细胞分化的机制研究

Several lines of evidences suggest that antigen specific T cells infiltration into tumors and maintenance of long lasting immune response can be key limiting factors for cancer immunotherapy. CD103 is increasingly recognized as a definitive marker of tissue resident memory T cells in various tissues. We have recently observed that CD103+T cells were highly enriched in the intra-tumor rather than the corresponding normal mucosa tissues of gastric cancer (GC). CD8+T cells, but not CD4+T cells, were the predominant cell type expressing CD103 in GC tissues. The accumulation of CD103+T cells in tumor tissues was negatively associated with disease progression in GC patients. Moreover, the density and the distribution of macrophages (Mφ) in GC tissues were significantly correlated with that of CD103+T cells. These results suggested that Mφ might constitute a novel mechanism to regulate the differentiation of CD103+T cells in GC. Based on these observations, we will use a combination of clinical samples, mouse model and experimental studies to: 1) Examine the phenotype and clinical significance of CD103+T cells in human GC. 2) Investigate the effect of CD103 expression for the anti-tumor and migratory activities of T cells in vivo. 3) Explore the key molecules and signaling pathways that regulate the differentiation of CD103+T cells by macrophage (Mφ) subsets. The results obtained from this project will not only reveal the molecular mechanisms about how Mφ regulate the development of CD103+T cells in GC, but also contribute to providing novel anti-cancer immunotherapy strategies by regulating CD103 expression on T cells.

抗肿瘤免疫治疗的关键是能有效维持抗原特异性T细胞进入肿瘤组织并产生持续的免疫应答。CD103是组织固有记忆性T细胞的特异性标记之一。我们新近发现：胃癌组织中存在大量CD103+T细胞的聚集，并且主要由CD8+T细胞而非CD4+T细胞表达；瘤内CD103+细胞的密度可预测患者良好的预后；此外，胃癌浸润巨噬细胞(Mφ)的数量和分布均与CD103+T细胞密切相关，提示：Mφ在组织中的聚集可能参与调节了CD103+T细胞的形成。以此为基础，本课题拟结合临床样本、小鼠模型和体外实验阐明胃癌组织中CD103+T细胞的表型及其对肿瘤进展的影响；研究CD103对T细胞抗肿瘤和体内迁移的作用；并探讨不同表型Mφ在诱导CD103+T细胞分化的作用及其调控的关键因子和信号通路。所得的结果将不仅有助于揭示肿瘤组织中CD103+T细胞分化的机制，还为以调控T细胞表达CD103为靶标的肿瘤免疫治疗提供理论基础。