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
单细胞转录组分析揭示超重和肥胖结直肠癌中的免疫抑制景观
英文原题：Single-cell transcriptome analysis reveals immunosuppressive landscape in overweight and obese colorectal cancer.
查看英文原题
Single-cell transcriptome analysis reveals immunosuppressive landscape in overweight and obese colorectal cancer.
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研究概要
研究表明，超重/肥胖的 CRC 具有更免疫抑制的微环境以及以糖酵解和脂质代谢增强为特征的独特代谢重编程。这些发现可能对为超重/肥胖 CRC 患者开发新型治疗策略具有重要意义。
研究思路结论见上方概要
背景
超重和肥胖是包括结直肠癌（CRC）在内的多种癌症的既定风险因素。然而，其潜在的分子机制仍不清楚。在单细胞水平上深入了解超重和肥胖CRC的肿瘤学特征，可为开发更有效的CRC治疗策略提供有价值的见解。
方法
我们对15名超重/肥胖和15名正常体重的CRC患者的肿瘤及邻近正常结直肠样本进行了单细胞RNA测序（scRNA-seq）分析。表征了超重/肥胖CRC与非肥胖CRC之间的免疫学和代谢差异。
结果
我们从所有样本中共获得192,785个细胞的单细胞转录组数据。通过评估标记基因表达模式，我们注释了CRC生态系统中九种主要细胞类型。具体而言，我们发现与非肥胖CRC相比，超重/肥胖CRC中效应T细胞和NK细胞的细胞毒性功能受损，这与其代谢失调相关。超重/肥胖CRC中的CD4+ T细胞表现出更高的免疫检查点分子表达。超重/肥胖CRC中DCs和B细胞的抗原呈递能力下调，这可能进一步加重超重/肥胖CRC的免疫抑制。此外，我们鉴定出功能失调的基质细胞，可能促进超重/肥胖CRC的侵袭和转移。进一步，我们发现超重/肥胖CRC中肿瘤细胞的糖酵解和脂质代谢上调，这可能影响免疫细胞的代谢和功能。我们还鉴定出超重/肥胖CRC中肿瘤细胞与T细胞之间的抑制性相互作用。
展开英文摘要原文
BACKGROUND
Overweight and obesity are established risk factors for various types of cancers including colorectal cancer (CRC). However the underlying molecular mechanisms remain unclear. An in-depth understanding of the oncologic characteristics of overweight and obese CRC at the single-cell level can provide valuable insights for the development of more effective treatment strategies for CRC.
METHODS
We conducted single-cell RNA sequencing (scRNA-seq) analysis on tumor and adjacent normal colorectal samples from 15 overweight/obese and 15 normal-weight CRC patients. Immunological and metabolic differences between overweight/obese CRC and non-obese CRC were characterized.
RESULTS
We obtained single-cell transcriptomics data from a total of 192,785 cells across all samples. By evaluating marker gene expression patterns, we annotated nine main cell types in the CRC ecosystem. Specifically, we found that the cytotoxic function of effector T cells and NK cells was impaired in overweight/obese CRC compared with non-obese CRC, relating to its metabolic dysregulation. CD4 + T cells in overweight/obese CRC exhibited higher expression of immune checkpoint molecules. The antigen-presenting ability of DCs and B cells is down-regulated in overweight/obese CRC, which may further aggravate the immunosuppression of overweight/obese CRC. Additionally, dysfunctional stromal cells were identified, potentially promoting invasion and metastasis in overweight/obese CRC. Furthermore, we discovered the up-regulated metabolism of glycolysis and lipids of tumor cells in overweight/obese CRC, which may impact the metabolism and function of immune cells. We also identified inhibitory interactions between tumor cells and T cells in overweight/obese CRC.
CONCLUSIONS
The study demonstrated that overweight/obese CRC has a more immunosuppressive microenvironment and distinct metabolic reprogramming characterized by increased of glycolysis and lipid metabolism. These findings may have implications for the development of novel therapeutic strategies for overweight/obese CRC patients.
论文信息
- 作者
- Xiao G、Zheng Y、Chen H、Luo M、Yang C、Ren D、Qin P、Zhang H
- 第一作者单位
- Department of General Surgery (Department of Coloproctology), The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510655, China.China
- 通讯作者单位
- Department of General Surgery (Department of Coloproctology), The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510655, China. lhcheng@mail.sysu.edu.cn.China
- 文献类型
- 非美国政府资助研究
- 期刊
- Journal of translational medicine2024 Feb 4
- 原文标识
- PubMed 38311726 · DOI 10.1186/s12967-024-04921-5
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