CD69+CD103+CD8+ tissue-resident memory T cells possess stronger anti-tumor activity and predict better prognosis in colorectal cancer.

IF 8.2 2区 生物学 Q1 CELL BIOLOGY
Zi-Xin Wu, Tian-Tian Da, Chuan Huang, Xiao-Qing Wang, Liang Li, Zhi-Bin Zhao, Ting-Ting Yin, Hai-Qing Ma, Zhe-Xiong Lian, Jie Long, Fei Wang, Jie Cao
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引用次数: 0

Abstract

Background: Colorectal cancer (CRC) is one of the most prevalent cancers worldwide. Despite advancements in therapeutic methodologies, it still causes a high rate of patient mortality. CD8+ tissue-resident memory T (TRM) cells are strategically positioned to mediate effective anti-tumor responses. However, the characteristic surface molecules and functions of CD8+ TRM cells exhibit significant heterogeneity.

Methods: The roles and anti-tumor biological functions of different CD8+ TRM subsets in CRC were determined by clinical CRC samples, bioinformatics analysis, and in vitro experiments including co-culture experiments and transwell migration assays. The signaling pathways that synergistically regulate the differentiation of CD8+ TRM cells were identified by in vitro CD8+ T cell activation and inhibition assays, and the functioning transcription factors were predicted using the UCSC and JASPAR databases.

Results: We found that different CD8+ TRM subsets existed in CRC tumor tissues, which were identified as CD69-CD103-CD8+ TRM, CD69+CD103-CD8+ TRM (SP CD8+ TRM), and CD69+CD103+CD8+ TRM (DP CD8+ TRM) subsets. Compared with SP CD8+ TRM cells, increased infiltration of DP CD8+ TRM cells predicted better prognosis and played a protective role mainly in tumor invasion and lymph node metastasis of CRC. DP CD8+ TRM cells expressed higher levels of effector molecules and exerted stronger anti-tumor effects in a FAS/FASL pathway-dependent manner. Additionally, DP CD8+ TRM cells secreted higher levels of CXCL13 and recruited B cells into tumor tissues through the CXCL13/CXCR5 signaling axis to form tertiary lymphoid structures, participating in anti-tumor immune responses. Notch and TGF-β signaling pathways synergistically regulate the differentiation of DP CD8+ TRM cells.

Conclusions: We clarified the roles and mechanisms of different CD8+ TRM subsets in CRC and identified that DP CD8+ TRM cells exert stronger anti-tumor effects and predict better prognosis, which provides ideas for developing new clinically available therapeutic targets.

CD69+CD103+CD8+组织驻留记忆T细胞在结直肠癌中具有较强的抗肿瘤活性和较好的预后。
背景:结直肠癌(CRC)是世界范围内最常见的癌症之一。尽管治疗方法取得了进步,但它仍然导致患者死亡率很高。CD8+组织驻留记忆T (TRM)细胞被战略性地定位于介导有效的抗肿瘤反应。然而,CD8+ TRM细胞的特征表面分子和功能表现出显著的异质性。方法:通过临床结直肠癌样本、生物信息学分析、体外共培养实验、transwell迁移实验等方法,确定不同CD8+ TRM亚群在结直肠癌中的作用和抗肿瘤生物学功能。通过体外CD8+ T细胞激活和抑制实验,确定了协同调节CD8+ TRM细胞分化的信号通路,并利用UCSC和JASPAR数据库预测了功能转录因子。结果:我们发现结直肠癌肿瘤组织中存在不同的CD8+ TRM亚群,分别鉴定为CD69-CD103-CD8+ TRM、CD69+CD103-CD8+ TRM (SP CD8+ TRM)和CD69+CD103+CD8+ TRM (DP CD8+ TRM)亚群。与SP CD8+ TRM细胞相比,DP CD8+ TRM细胞浸润增加预示着更好的预后,并主要在结直肠癌的肿瘤侵袭和淋巴结转移中发挥保护作用。DP CD8+ TRM细胞表达更高水平的效应分子,并以FAS/FASL通路依赖的方式发挥更强的抗肿瘤作用。此外,DP CD8+ TRM细胞分泌更高水平的CXCL13,并通过CXCL13/CXCR5信号轴募集B细胞进入肿瘤组织,形成三级淋巴样结构,参与抗肿瘤免疫应答。Notch和TGF-β信号通路协同调节DP CD8+ TRM细胞的分化。结论:我们明确了不同CD8+ TRM亚群在结直肠癌中的作用和机制,发现DP CD8+ TRM细胞具有更强的抗肿瘤作用,预测更好的预后,为开发新的临床可用的治疗靶点提供思路。
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来源期刊
CiteScore
11.00
自引率
0.00%
发文量
180
期刊介绍: Cell Communication and Signaling (CCS) is a peer-reviewed, open-access scientific journal that focuses on cellular signaling pathways in both normal and pathological conditions. It publishes original research, reviews, and commentaries, welcoming studies that utilize molecular, morphological, biochemical, structural, and cell biology approaches. CCS also encourages interdisciplinary work and innovative models, including in silico, in vitro, and in vivo approaches, to facilitate investigations of cell signaling pathways, networks, and behavior. Starting from January 2019, CCS is proud to announce its affiliation with the International Cell Death Society. The journal now encourages submissions covering all aspects of cell death, including apoptotic and non-apoptotic mechanisms, cell death in model systems, autophagy, clearance of dying cells, and the immunological and pathological consequences of dying cells in the tissue microenvironment.
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