RNF43 p.G659fs 通过 PI3K/AKT/mTOR 信号通路和 HLA-E 上调导致 MSI-high 结直肠癌中 NK 细胞功能障碍
RNF43 p.G659fs leads to natural killer cell dysfunction in MSI-high colorectal cancer through PI3K/AKT/mTOR signaling and HLA-E up-regulation.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
Lypd6b 缺失通过代谢重编程促进结直肠癌中 CD8(+) T 细胞介导的抗肿瘤免疫
英文原题：Lypd6b depletion promotes CD8(+) T cell-mediated anti-tumor immunity via metabolic reprogramming in colorectal cancer.
查看英文原题
Lypd6b depletion promotes CD8(+) T cell-mediated anti-tumor immunity via metabolic reprogramming in colorectal cancer.
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中文摘要
淋巴细胞抗原-纤溶酶原激活物尿激酶受体结构域包含蛋白6B（Lypd6b）是一种新发现的与神经调控相关的分子。然而，Lypd6b在调控肿瘤微环境中的作用及其对CD8+ T细胞介导的抗肿瘤免疫的影响仍不清楚。
在此，我们观察到与正常组织相比，Lypd6b在结直肠癌（CRC）肿瘤组织中的表达显著增加。Lypd6b主要表达于肿瘤组织中的CD8+ T细胞。Lypd6b敲除（Lypd6b-/-）小鼠对AOM/DSS诱导的肿瘤发生具有抵抗性。
此外，Lypd6b的整体缺失或CD8+细胞缺失可抑制MC38或CMT-93肿瘤生长并促进CD8+ T细胞的浸润。机制上，Lypd6b缺失以PI3K/mTOR/LDHA通路依赖的方式促进CD8+ T细胞在抗肿瘤反应中的活化和功能，伴随糖酵解增加和氧化磷酸化减少。
值得注意的是，Lypd6b缺失的CD8+ T细胞与抗PD1抗体联合使用时具有更强的抗肿瘤效果。因此，Lypd6b作为T细胞免疫的负调控因子促进CRC发展，提供了一个具有CRC治疗潜力的分子靶点。
展开英文摘要原文
Lymphocyte antigen-plasminogen activator urokinase receptor domain-containing protein 6B (Lypd6b) is a newly identified molecule associated with neuromodulation.
However, the role of Lypd6b in regulating the tumor microenvironment and its impact on CD8 + T cell-mediated antitumor immunity remain unknown.
Here, we observe that Lypd6b expression is increased significantly in colorectal cancer (CRC) tumor tissues compared to normal tissues. Lypd6b is mainly expressed in CD8 + T cells in tumor tissues. Lypd6b knockout (Lypd6b -/- ) mice are resistant to AOM/DSS-induced tumorigenesis.
Furthermore, global deficiency or CD8 + cell deficiency of Lypd6b inhibits MC38 or CMT-93 tumor growth and promotes the infiltration of CD8 + T cells.
Mechanistically, Lypd6b deficiency promotes activation and function of CD8 + T cells in anti-tumor response with increased glycolysis and reduced oxidative phosphorylation in a PI3K/mTOR/LDHA pathway-dependent manner.
Notably, Lypd6b deficient CD8 + T cells have a more potent antitumor effect when combined with anti-PD1 antibody.
Thus, Lypd6b as a negative regulator for T cell immunity promotes CRC development, providing a molecular target with therapeutic potential in CRC.
论文信息
- 作者
- Liu T、Zeng F、Li Z、Cheng L、Yan X、Chen H、Liu Q、Li X
- 第一作者单位
- The College of Life Science and Bioengineering, Beijing Jiaotong University, Beijing, China.China
- 通讯作者单位
- The College of Life Science and Bioengineering, Beijing Jiaotong University, Beijing, China. zhangjh@bjtu.edu.cn.China
- 期刊
- Nature communications2025 Dec 11
- 原文标识
- PubMed 41381524 · DOI 10.1038/s41467-025-67344-w
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