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
不同的 NK 细胞特征定义了 HPV 阳性与 HPV 阴性头颈癌的预后
英文原题：Distinct NK Cell Signatures Define Prognosis in HPV-Positive Versus HPV-Negative Head and Neck Cancer.
查看英文原题
Distinct NK Cell Signatures Define Prognosis in HPV-Positive Versus HPV-Negative Head and Neck Cancer.
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中文摘要
方法
我们对已发表的 28 例 HNSCC 患者（10 例 HPV+，18 例 HPV-；GEO：GSE139324、GSE164690）的 scRNA-seq 数据进行了以 NK 细胞为中心的重分析，涵盖 NK 亚群鉴定、拟时序轨迹推断和细胞间相互作用分析。关键发现通过免疫组织化学（IHC）在独立队列的 10 例 FFPE 组织切片中进行了验证，并使用 TCGA-HNSC 数据评估了预后相关性。
结果
鉴定出四个转录上不同的 NK 细胞亚群：适应性、细胞杀伤性、CD56 bright 和病毒反应性。一个细胞毒性 CX3CR1+ KLRB1 dim NK 亚群在 HPV+ 肿瘤中特异性富集，并与良好生存独立相关。相反，HPV- 肿瘤上调肿瘤细胞表面的 CLEC2C 和 CLEC2D 配体，与 NK 细胞上的抑制性受体 KLRB1 结合；该 CLEC2-KLRB1 轴与 NK 活性受抑和较差预后相关，并通过 IHC 在蛋白水平得到证实。
结论
HNSCC 中 NK 细胞功能受 HPV 状态的双向调控。CX3CR1+ KLRB1 dim 亚群是 HPV+ 疾病中候选的预后生物标志物，而 CLEC2-KLRB1 轴是 HPV- HNSCC 中可靶向的免疫逃逸机制。这些见解支持HPV分层免疫疗法的开发；然而，临床转化需要在大型、前瞻性设计、亚部位匹配的队列中进行验证，以将HPV特异性效应与解剖部位依赖性免疫微环境区分开来。
展开英文摘要原文
Background/Objectives: HPV status is a key prognostic determinant in head and neck squamous cell carcinoma (HNSCC), yet the immunological mechanisms underlying the survival advantage of HPV-positive (HPV + ) over HPV-negative (HPV - ) disease remain poorly defined.
This study aimed to characterize the tumor-infiltrating natural killer (NK) cell landscape in HPV-stratified HNSCC and identify novel therapeutic targets. Methods: We performed an NK-cell-centric re-analysis of published scRNA-seq data from 28 HNSCC patients (10 HPV + , 18 HPV - ; GEO: GSE139324, GSE164690), encompassing NK subset identification, pseudotime trajectory inference, and cell-cell interaction analysis. Key findings were validated by immunohistochemistry (IHC) in an independent cohort of 10 FFPE tissue sections, and prognostic associations were assessed using TCGA-HNSC data. Results: Four transcriptionally distinct NK cell subsets were identified: adaptive, cell-killing, CD56 bright , and virus-responsive. A cytotoxic CX3CR1 + KLRB1 dim NK subset was specifically enriched in HPV + tumors and independently associated with favorable survival.
Conversely, HPV - tumors upregulated CLEC2C and CLEC2D ligands on tumor cell surfaces, engaging the inhibitory receptor KLRB1 on NK cells; this CLEC2-KLRB1 axis correlated with suppressed NK activity and poorer prognosis, and was confirmed at the protein level by IHC. Conclusions: NK cell function in HNSCC is dichotomously regulated by HPV status.
The CX3CR1 + KLRB1 dim subset represents a candidate prognostic biomarker in HPV + disease, and the CLEC2-KLRB1 axis is a targetable immune evasion mechanism in HPV - HNSCC. These insights support the development of HPV-stratified immunotherapies; however, clinical translation requires validation in large, prospectively designed, subsite-matched cohorts to disentangle HPV-specific effects from anatomical site-dependent immune contextures.
论文信息
- 作者
- Li R、Tong F、Liu H、Liu Z、Li W、Zhang Y、Peng Y、Pan S
- 单位
- Department of Neurosurgery, Shenzhen Third People's Hospital, The Second Hospital Affiliated to Southern University of Science and Technology, Shenzhen 518112, China.China
- 期刊
- Cancers2026 Mar 5
- 原文标识
- PubMed 41827778 · DOI 10.3390/cancers18050845
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