间皮素作为癌症免疫治疗的生物标志物和治疗靶点
Mesothelin as Biomarker and Therapeutic Target for Immunotherapy in Cancer.
癌症仍是一个关键的全球健康问题，原因在于发现晚、耐药和高死亡率。
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
三级淋巴结构相关 B 细胞增强 CXCL13(+)CD103(+)CD8(+) 组织驻留记忆 T 细胞对程序性细胞死亡蛋白 1 阻断在癌症免疫治疗中的应答
英文原题：Tertiary Lymphoid Structure-Associated B Cells Enhance CXCL13(+)CD103(+)CD8(+) Tissue-Resident Memory T-Cell Response to Programmed Cell Death Protein 1 Blockade in Cancer Immunotherapy.
查看英文原题
Tertiary Lymphoid Structure-Associated B Cells Enhance CXCL13(+)CD103(+)CD8(+) Tissue-Resident Memory T-Cell Response to Programmed Cell Death Protein 1 Blockade in Cancer Immunotherapy.
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中文摘要
背景与目的
尽管在许多实体瘤中，三级淋巴结构（TLS）的存在与免疫治疗的良好应答相关，但TLS增强抗肿瘤免疫的机制尚不清楚。本研究旨在探究TLS内B细胞与组织驻留记忆T（Trm）细胞之间的相互作用回路，并理解其在免疫治疗中的作用。
方法
对胃癌（GC）患者肿瘤切片中的TLS及趋化因子（C-X-C基序）配体13（CXCL13）⁺ CD103⁺ CD8⁺ Trm细胞进行免疫染色和苏木精-伊红染色。在体外和体内确定B细胞与CXCL13⁺ CD103⁺ CD8⁺ Trm细胞之间的通讯机制。通过抗程序性细胞死亡蛋白1（PD-1）治疗评估CXCL13⁺ CD103⁺ CD8⁺ Trm细胞抑制肿瘤生长的作用。
结果
胃癌患者肿瘤组织中存在TLS和CXCL13⁺ CD103⁺ CD8⁺ Trm细胞，与抗PD-1治疗的较佳应答相关。此外，研究发现活化B细胞可增强CD103⁺ CD8⁺ Trm细胞分泌CXCL13和颗粒酶B。从机制上看，B细胞通过淋巴毒素α/肿瘤坏死因子受体2（TNFR2）轴促进CD103⁺ CD8⁺ Trm细胞糖酵解；在这一过程中，雷帕霉素靶蛋白信号通路对这些细胞的糖酵解发挥关键作用。此外，TLS和CXCL13⁺ CD103⁺ CD8⁺ Trm细胞的存在，与TNFR2依赖性的抗PD-1治疗强效应答相关。
结论
本研究进一步揭示了TLS相关B细胞与CXCL13⁺ CD103⁺ CD8⁺ Trm细胞之间的细胞通讯在抗肿瘤免疫中的关键作用，并提示靶向CXCL13⁺ CD103⁺ CD8⁺ Trm细胞内的淋巴毒素α/TNFR2轴，可能为推进胃癌免疫治疗策略提供有价值的思路。
展开英文摘要原文
METHODS
Immunostaining and H&E staining of TLS and chemokine (C-X-C motif) ligand 13 (CXCL13) + cluster of differentiation (CD)103 + CD8 + Trm cells were performed on tumor sections from patients with gastric cancer (GC). The mechanism of communication between B cells and CXCL13 + CD103 + CD8 + Trm cells was determined in vitro and in vivo. The effect of CXCL13 + CD103 + CD8 + Trm cells in suppressing tumor growth was evaluated through anti-programmed cell death protein (PD)-1 therapy.
RESULTS
The presence of TLS and CXCL13 + CD103 + CD8 + Trm cells in tumor tissues favored a superior response to anti-PD-1 therapy in patients with GC. Additionally, our research identified that activated B cells enhanced CXCL13 and granzyme B secretion by CD103 + CD8 + Trm cells. Mechanistically, B cells facilitated the glycolysis of CD103 + CD8 + Trm cells through the lymphotoxin-α/tumor necrosis factor receptor 2 (TNFR2) axis, and the mechanistic target of rapamycin signaling pathway played a critical role in CD103 + CD8 + Trm cells glycolysis during this process. Moreover, the presence of TLS and CXCL13 + CD103 + CD8 + Trm cells correlated with potent responsiveness to anti-PD-1 therapy in a TNFR2-dependent manner.
CONCLUSIONS
This study further reveals a crucial role for cellular communication between TLS-associated B cell and CXCL13 + CD103 + CD8 + Trm cells in antitumor immunity, providing valuable insights into the potential use of the lymphotoxin-α/TNFR2 axis within CXCL13 + CD103 + CD8 + Trm cells for advancing immunotherapy strategies in GC.
论文信息
- 作者
- Hu C、You W、Kong D、Huang Y、Lu J、Zhao M、Jin Y、Peng R
- 第一作者单位
- Department of General Surgery, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China; The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Wuxi, China; Department of Immunology, School of Basic Medical Sciences, Wuxi Medical Center, Nanjing Medical University, Nanjing, China; The Affiliated Huai'an No. 1 People's Hospital, Nanjing Medical University, Nanjing, China; Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.China
- 通讯作者单位
- Department of General Surgery, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China; The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Wuxi, China; Department of Immunology, School of Basic Medical Sciences, Wuxi Medical Center, Nanjing Medical University, Nanjing, China; The Affiliated Huai'an No. 1 People's Hospital, Nanjing Medical University, Nanjing, China; Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China. Electronic address: chenyun@njmu.edu.cn.China
- 文献类型
- 非美国政府资助研究
- 期刊
- Gastroenterology2024 Jun
- 原文标识
- PubMed 38445519 · DOI 10.1053/j.gastro.2023.10.022