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
肿瘤微环境中共表达颗粒酶 A 和 IFN-γ 的 CD8⁺ TILs 与结肠癌细胞的关联
英文原题：Association of CD8(+)TILs co-expressing granzyme A and interferon-γ with colon cancer cells in the tumor microenvironment.
查看英文原题
Association of CD8(+)TILs co-expressing granzyme A and interferon-γ with colon cancer cells in the tumor microenvironment.
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中文摘要
分泌颗粒酶A（GZMA）的CD8阳性T细胞可在干扰素γ刺激下切割Gasdermin B（GSDMB），诱导肿瘤细胞焦亡；但在结肠癌中两者相互作用尚不清楚。本研究结合多重免疫组化、临床资料和单细胞RNA测序，分析人结肠癌微环境中表达GZMA及干扰素γ的CD8阳性TIL与表达GSDMB的细胞分布及临床意义。单细胞分析显示，GZMA和干扰素γ共表达于CD8 TIL。患者肿瘤中双阳性CD8 TIL浸润显著减少，但其活化和效应功能强于其他亚群。表达GSDMB的肿瘤细胞免疫原性增强，两类细胞数量呈正相关。细胞互作分析提示该联系涉及干扰素γ、TGF-β、共刺激分子ICOS及检查点TIGIT和TIM-3。结果提示双阳性CD8 TIL可调节GSDMB阳性肿瘤细胞，影响结肠癌免疫微环境及患者预后，为开发免疫治疗提供新线索。
展开英文摘要原文
CD8 + T cells secreting granzyme A (GZMA) can induce pyroptosis in tumor cells by effectively cleaving gasdermin B (GSDMB), which is stimulated by interferon- (IFN- ).
However, the interaction between GZMA-expressing CD8 + T cells and GSDMB-expressing tumor cells in colon cancer remains poorly understood.
Our research employed multi-color immunohistochemistry (mIHC) staining and integrated clinical data to explore the spatial distribution and clinical relevance of GZMA- and IFN- -expressing CD8 + tumor-infiltrating lymphocytes (TILs), as well as GSDMB-expressing CK + cells, within the tumor microenvironment (TME) of human colon cancer samples.
Additionally, we utilizing single-cell RNA sequencing (scRNA-seq) data to examine the functional dynamics and interactions among these cell populations. scRNA-seq analysis of colorectal cancer (CRC) tissues revealed that CD8 + TILs co-expressed GZMA and IFN- , but not other cell types.
Our mIHC staining results indicated that a significant reduction in the infiltration of GZMA + IFN- + CD8 + TILs in colon cancer patients (P < 0. 01). Functional analysis results indicated that GZMA + IFN- + CD8 + TILs demonstrated enhanced activation and effector functions compared to other CD8 + TIL subsets.
Furthermore, GSDMB-expressing CK + cells exhibited augmented immunogenicity. Correlation analysis highlighted a positive association between GSDMB + CK + cells and GZMA + IFN- + CD8 + TILs (r = 0. 221, P = 0. 033). Analysis of cell-cell interactions further showed that these interactions were mediated by IFN- and transforming growth factor- (TGF- ), the co-stimulatory molecule ICOS, and immune checkpoint molecules TIGIT and TIM-3.
These findings suggested that GZMA + IFN- + CD8 + TILs modulating GSDMB-expressing tumor cells, significantly impacted the immune microenvironment and patients' prognosis in colon cancer. By elucidating these mechanisms, our present study aims to provide novel insights for the advancement of immunotherapeutic strategies in colon cancer.
论文信息
- 作者
- Yang J、Ding X、Fang Z、Wu S、Yuan M、Chen R、Xu Q、Gao X
- 第一作者单位
- Department of Tumor Biological Treatment, the Third Affiliated Hospital of Soochow University, Jiangsu Changzhou, Jiangsu, 213003, China.China
- 通讯作者单位
- Department of Tumor Biological Treatment, the Third Affiliated Hospital of Soochow University, Jiangsu Changzhou, Jiangsu, 213003, China. jiangjingting@suda.edu.cn.China
- 期刊
- BMC cancer2024 Jul 19
- 原文标识
- PubMed 39030523 · DOI 10.1186/s12885-024-12605-y
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