免疫细胞表面分子TIM-3/CEACAM1共表达对结直肠癌的诊断及预后研究

Upregulation of TIM-3 is associated with immune escape. It has been reported that CEACAM1 can regulate T cell exhaustion via TIM-3 molecule, which will lead to the immune tolerance of tumors. Our previous work indicated that TIM-3 and CEACAM1 were co-expressed on the circulating CD8+ T cells and tumor-infiltrating lymphocytes, which would cause T cell exhaustion of colorectal cancer (CRC) patients, and we showed that the number of T cells which co-expressed TIM-3 and CEACAM1 in metastasis CRC patients was much more than that in those CRC patients without metastasis. Herein, we propose to analyze the peripheral blood samples and primary/metastatic tumor lesions to reveal the expression differences of T cells in CRC with/without metastasis. Thus then we can set up a model for CRC prediction. And also, we will co-culture T cells and CRC cell line and utilize metastatic CRC mouse models to analyze the influence of TIM-3/CEACAM1 on the proliferation, metastasis and prognosis of CRC to find potential targets for the immunotherapy of metastatic CRC.

免疫检查点TIM-3上调和肿瘤的免疫逃避密切相关，CEACAM1作为TIM-3的异嗜性配体，可以调控TIM-3介导的T细胞耗竭，致肿瘤免疫耐受。申请者前期研究发现：TIM-3和CEACAM1在结直肠癌患者的循环CD8+T细胞及肿瘤组织的肿瘤浸润淋巴细胞上存在共表达，介导了结直肠癌病人的T细胞功能耗竭，同时TIM-3/CEACAM1共表达的T细胞比例在结直肠癌远处转移患者中明显高于无远处转移患者。因此，本项目通过检测结直肠癌病人外周血、原发灶及转移灶临床标本，分析TIM-3及CEACAM1在未/已转移结直肠癌T细胞中表达的差异，并建立TIM-3/CEACAM1对结直肠癌的预测模型。通过结直肠癌细胞系与T细胞共培养体系、小鼠结直肠癌转移模型等体内外模型，探讨TIM-3/CEACAM1对肿瘤生长，转移及预后的影响，为结直肠癌转移的免疫治疗提供潜在的新靶点。

T细胞免疫球蛋白粘蛋白(TIM)-3阻断可改善T细胞衰竭并触发树突状细胞(DC)炎症小体激活，在免疫检查点阻断(ICB)免疫治疗中显示出巨大潜力。然而，肿瘤微环境中的药代动力学特征和T细胞/DC浸润仍不理想。因此，我们团队开发了一种水凝胶加载长非编码RNA (lncRNA)编辑的仿生纳米疫苗，结合TIM-3阻断剂抑制围手术期结直肠癌(CRC)复发和转移。LncRNA诱导主要组织相容性复合物-I和肿瘤(LIMIT)编辑的CRC细胞膜(CC)的免疫原性被用来包封抗tim -3，形成LCCT。之后，LCCT被嵌入到透明质酸和海藻酸盐基水凝胶中，用于术后植入。LCCT在很大程度上仍然是抗TIM-3的封锁效果。此外，集成的anti-TIM-3增强了DCs中LCCT的内吞作用(1.5倍)，放大了炎性小体的激活和抗原交叉呈递。此外，这种与LCCT诱导的CD8+ T细胞的DC激活协同抑制了免疫抑制和交叉提呈刺激效应子和记忆前体CD8+ T细胞对抗CRCs。这种lncRNA编辑的仿生纳米疫苗策略为改进目前的ICB免疫治疗带来了新的前景。