CD8<sup>+</sup>肿瘤浸润淋巴细胞中TIGIT与TNFRSF9的共同表达增加与结直肠癌不良预后和免疫治疗反应改善的关系-东南大学学报医学版

CD8⁺肿瘤浸润淋巴细胞中TIGIT与TNFRSF9的共同表达增加与结直肠癌不良预后和免疫治疗反应改善的关系

单位：新疆医科大学附属肿瘤医院新疆肿瘤学重点实验室/中国医学科学院肿瘤免疫治疗与放疗重点实验室/新疆维吾尔自治区卫健委放射治疗临床重点专科/新疆肿瘤放射治疗临床研究培育中心, 新疆乌鲁木齐 830011

关键词：免疫治疗生物标志物结直肠癌 T细胞免疫球蛋白与ITIM结构域蛋白诱导共刺激分子肿瘤坏死因子受体超家族成员9

分类号：R735.3

出版年·卷·期（页码）：2025·44·第五期（697-710）

摘要：

目的:探讨T细胞免疫球蛋白与ITIM结构域蛋白(TIGIT)、诱导共刺激分子(ICOS)和肿瘤坏死因子受体超家族成员9(TNFRSF9)在肿瘤免疫微环境中的作用,评估其共表达对结直肠癌患者预后和免疫治疗响应的影响,并揭示潜在的耐药机制。方法:分析新疆医科大学附属肿瘤医院32对结直肠癌患者癌/癌旁组织、19例外周血样本及基因表达综合数据库(GEO)20例单细胞转录组数据,结合GEO与癌症基因组图谱(TCGA)数据库,进行多因素回归及生存分析。使用CellChat和SCENIC方法验证配体-受体信号及转录因子激活。结果:TIGIT-ICOS共表达在肿瘤组织CD8⁺ T细胞中显著升高,并与肿瘤位置相关(P<0.05);TIGIT-TNFRSF9共表达与免疫治疗的完全缓解率和肿瘤退缩率相关(P<0.05);TIGIT-TNFRSF9共表达亚群中EB病毒诱导基因3(EBI3)显著上调(P<0.000 1),可能抑制CD8⁺ T细胞功能。生存分析显示,TIGIT-TNFRSF9共表达标记基因心肌型雷诺受体钙通道2(RYR2)和驱动蛋白家族成员7(KIF7)为患者不良预后的独立风险因子(P<0.01)。结论:TIGIT-TNFRSF9共表达在结直肠癌免疫微环境中具有重要作用,并与预后及免疫治疗响应密切相关,提示其为潜在的免疫治疗靶点。

Objective: To investigate the roles of T cell immunoreceptor with Ig and ITIM domains(TIGIT), inducible T-cell costimulator(ICOS), and tumor necrosis factor receptor superfamily member 9(TNFRSF9) in the tumor immune microenvironment, evaluate the prognostic significance and immunotherapy response implications of their co-expression in colorectal cancer(CRC) patients, and reveal potential mechanisms of resistance. Methods: We analyzed 32 paired cancer and adjacent tissues from CRC patients, along with 19 peripheral blood samples from the Affiliated Tumor Hospital of Xinjiang Medical University, and 20 single-cell transcriptome datasets from the gene expression omnibus(GEO) database. Combining GEO and the cancer genome atlas(TCGA) databases, we performed multivariate regression and survival analyses. CellChat and SCENIC analyses were used to validate ligand-receptor signaling interactions and transcription factor activation. Results: TIGIT-ICOS co-expression was significantly increased in tumor-infiltrating CD8⁺ T cells and correlated with tumor location(P<0.05). The co-expression of TIGIT-TNFRSF9 was significantly associated with complete response rates and tumor regression following immunotherapy(P<0.05). Furthermore, the TIGIT-TNFRSF9 co-expression subgroup exhibited a significant upregulation of Epstein-Barr virus-induced gene 3(EBI3)(P<0.000 1), potentially inhibiting CD8⁺ T cell functionality. Survival analysis identified the co-expression markers Ryanodine receptor 2(RYR2) and kinesin family member 7(KIF7) as independent risk factors for poor prognosis(P<0.01). Conclusion: TIGIT-TNFRSF9 co-expression plays an important role in the CRC immune microenvironment, correlating closely with prognosis and response to immunotherapy, suggesting its potential as an immunotherapeutic target.

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