肿瘤内CD8 CXCR5滤泡细胞毒性T细胞具有预后价值，且与结直肠癌中的CD19 CD38 B细胞及三级淋巴结构相关。
Intratumoural CD8 CXCR5 follicular cytotoxic T cells have prognostic value and are associated with CD19 CD38 B cells and tertiary lymphoid structures in colorectal cancer.
作者信息
Wei Fangze, Xu Xiaotian, Wang Jing, Mei Shi Wen, Zhao Fu Qiang, Huang Fei, Xiao Ti Xian, Wang Guo Jing, Wei Baojun, Huang Shengkai, Cui Wei
机构信息
Department of Clinical Laboratory, State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
出版信息
Cancer Immunol Immunother. 2024 Dec 30;74(1):36. doi: 10.1007/s00262-024-03887-z.
BACKGROUND
Colorectal cancer (CRC) is the most common digestive cancer in the world. Microsatellite stability (MSS) and microsatellite instability (MSI-high) are important molecular subtypes of CRC closely related to tumor occurrence and progression and immunotherapy efficacy. The presence of CD8 CXCR5 follicular cytotoxic T (T) cells is strongly associated with autoimmune disease and CD8 effector function. However, the roles of T cells in MSI-high CRC and MSS CRC are unclear. Here, we aimed to explore the characteristics of T cells in CRC and compare their biological functions between MSI-high and MSS CRC.
METHODS
We explored the expression of T cell in tumor tissues and peripheral blood in our clinical cohort and public datasets. By combining single-cell RNA sequencing (scRNA-seq) and bulk RNA sequencing, we explored the potential function of T cells and developed a prediction model for CRC. We also compared the biological functions of these cells between MSS and MSI-high CRC and used flow cytometry and coculture experiments to explore their potential regulatory functions.
RESULTS
T cell markers are downregulated in tumor tissues and patient peripheral blood vs. controls. The prediction model for CRC performed well in the training and validation cohorts (KM plot p < 0.001). MSS CRC patients exhibit enrichment of genes related to the cell cycle (MKI67) and T cell activation (CD38 and HLA-DR) and decreased enrichment of immune checkpoint markers (PD1, TIM3, and LAG3). The expression of T cell-related genes is positively correlated with that of CD8IFN-γ-related genes and closely related to that of TLS-related genes in MSS CRC. The proportion of T cells is positively correlated with that of CD19CD38 B cells in MSS CRC.
CONCLUSIONS
The prognostic prediction model has good predictive value. In MSS CRC, T cells function mostly in T cell activation and the cell cycle and have low expression of immune checkpoint molecules, which may influence the effectiveness of ICB therapy. T cells may regulate antitumor function by regulating CD19 CD38 B cells and TLSs.
背景
结直肠癌（CRC）是世界上最常见的消化系统癌症。微卫星稳定性（MSS）和微卫星不稳定性（MSI-高）是CRC重要的分子亚型，与肿瘤发生、进展及免疫治疗疗效密切相关。CD8 CXCR5滤泡细胞毒性T细胞的存在与自身免疫性疾病及CD8效应功能密切相关。然而，T细胞在MSI-高的CRC和MSS CRC中的作用尚不清楚。在此，我们旨在探索CRC中T细胞的特征，并比较MSI-高和MSS CRC之间T细胞的生物学功能。
方法
我们在临床队列和公共数据集中探索肿瘤组织和外周血中T细胞的表达。通过结合单细胞RNA测序（scRNA-seq）和批量RNA测序，我们探索了T细胞的潜在功能，并建立了CRC的预测模型。我们还比较了MSS和MSI-高的CRC之间这些细胞的生物学功能，并使用流式细胞术和共培养实验来探索它们的潜在调节功能。
结果
与对照组相比，肿瘤组织和患者外周血中的T细胞标志物下调。CRC的预测模型在训练和验证队列中表现良好（KM图p<0.001）。MSS CRC患者表现出与细胞周期相关基因（MKI67）和T细胞活化相关基因（CD38和HLA-DR）的富集，以及免疫检查点标志物（PD1、TIM3和LAG3）的富集减少。在MSS CRC中，T细胞相关基因的表达与CD8 IFN-γ相关基因的表达呈正相关，且与TLS相关基因的表达密切相关。在MSS CRC中，T细胞比例与CD19 CD38 B细胞比例呈正相关。
结论
该预后预测模型具有良好的预测价值。在MSS CRC中，T细胞主要在T细胞活化和细胞周期中发挥作用，免疫检查点分子表达较低，这可能影响ICB治疗的有效性。T细胞可能通过调节CD19 CD38 B细胞和TLS来调节抗肿瘤功能。
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