肿瘤细胞治疗研究
英文原题：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.
该预后预测模型具有良好的预测价值。在MSS CRC中，T FC细胞主要在T细胞活化和细胞周期中发挥作用，且免疫检查点分子低表达，这可能影响ICB治疗的疗效。T FC细胞可能通过调控CD19 + CD38 + B细胞和TLSs来调节抗肿瘤功能。
结直肠癌（CRC）是全球最常见的消化道肿瘤。微卫星稳定（MSS）和微卫星高度不稳定（MSI-high）是与肿瘤发生发展及免疫治疗疗效密切相关的CRC重要分子亚型。CD8+CXCR5+滤泡细胞毒性T（TFC）细胞的存在与自身免疫性疾病和CD8+效应功能密切相关。然而，TFC细胞在MSI-high CRC和MSS CRC中的作用尚不清楚。在此，我们旨在探索TFC细胞在CRC中的特征，并比较其在MSI-high和MSS CRC中的生物学功能。
我们探索了T FC细胞在临床队列和公共数据集肿瘤组织及外周血中的表达。通过结合单细胞RNA测序（scRNA-seq）和bulk RNA测序，我们探索了T FC细胞的潜在功能，并开发了CRC的预测模型。我们还比较了这些细胞在MSS和MSI-high CRC中的生物学功能，并使用流式细胞术和共培养实验探索了其潜在的调控功能。
T FC 细胞标志物在肿瘤组织和患者外周血中较对照组下调。CRC 预测模型在训练队列和验证队列中表现良好（KM 曲线 p < 0.001）。MSS CRC 患者表现出细胞周期相关基因（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）富集的降低。在 MSS CRC 中，T FC 细胞相关基因的表达与 CD8 + IFN-γ + 相关基因的表达呈正相关，并与 TLS 相关基因的表达密切相关。在 MSS CRC 中，T FC 细胞的比例与 CD19 + CD38 + B 细胞的比例呈正相关。
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 FC ) cells is strongly associated with autoimmune disease and CD8 + effector function. However, the roles of T FC cells in MSI-high CRC and MSS CRC are unclear. Here, we aimed to explore the characteristics of T FC cells in CRC and compare their biological functions between MSI-high and MSS CRC. METHODS: We explored the expression of T FC 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 FC 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 FC 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 FC cell-related genes is positively correlated with that of CD8 + IFN-γ + -related genes and closely related to that of TLS-related genes in MSS CRC. The proportion of T FC cells is positively correlated with that of CD19 + CD38 + B cells in MSS CRC. CONCLUSIONS: The prognostic prediction model has good predictive value. In MSS CRC, T FC 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 FC cells may regulate antitumor function by regulating CD19 + CD38 + B cells and TLSs.
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