CELL INTELLIGENCE · 肿瘤细胞治疗研究

CELLIN 肿瘤细胞治疗研究

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单细胞分析揭示了一个缺氧-血管-免疫轴，是非肢端型与肢端型黑色素瘤免疫治疗反应差的基础

英文原题：Single-cell profiling uncovers a hypoxia-vascular-immune axis underlying poor immunotherapy response in acral versus cutaneous melanoma.

查看英文原题

Single-cell profiling uncovers a hypoxia-vascular-immune axis underlying poor immunotherapy response in acral versus cutaneous melanoma.

PubMed 2026/05/07（内容时间） J Transl Med Q1 · IF 9.7（JCR 2025）

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黑色素瘤地区：中国
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研究概要

本研究为 AM 中与免疫治疗耐药相关的血管-基质特征提供了见解，突出 RGS5 + /COL3A1 + 周细胞和 NECTIN2-TIGIT 轴作为靶点，并指导 AM 有效联合免疫疗法的开发。

研究思路结论见上方概要

背景

肢端黑色素瘤（AM）约占亚洲人群黑色素瘤的50%，其免疫治疗缓解率远低于皮肤黑色素瘤（CM，约43.7%），抗PD-1 ORR<20%。尽管肿瘤微环境（TME）在免疫治疗耐药中起关键作用，但既往研究主要聚焦于免疫细胞，忽视了血管周细胞等基质成分，这在理解AM治疗抵抗方面造成了关键的知识空白。

方法

我们整合了来自31例肢端黑色素瘤、13例皮肤黑色素瘤和35例正常皮肤样本的多个单细胞转录组数据集。进行了包括细胞类型注释、差异表达、基因功能富集和细胞-细胞相互作用分析在内的综合生物信息学分析，以描绘肢端黑色素瘤与皮肤黑色素瘤之间的肿瘤微环境差异。关键发现通过空间转录组学、bulk RNA-seq数据集以及包括qPCR和western blot在内的功能实验进行了验证。

结果

AM具有更强的免疫抑制性TME，富含分泌胶原的RGS5+/COL3A1+周细胞，这些细胞与KDR+/PODXL+内皮细胞共定位，与血管异常和缺氧相关。这些分泌胶原的RGS5+/COL3A1+周细胞（在AM中富集）与CD8+TIL（肿瘤浸润淋巴细胞）（TILs）的浸润比例呈显著负相关；此外，在免疫治疗队列中，分泌胶原的周细胞标志物RGS5高表达与对免疫检查点阻断（ICB）治疗反应较差相关。我们还发现了一个与缺氧相关的NECTIN2-TIGIT免疫抑制轴：缺氧上调多种细胞上的NECTIN2，与T细胞上的TIGIT相互作用，可能加剧功能障碍。

展开英文摘要原文
BACKGROUND

Acral melanoma (AM), accounting for ~50% of melanomas in Asian populations, exhibits far poorer immunotherapy response (anti-PD-1 ORR < 20%) than cutaneous melanoma (CM, ~43.7%). While the tumor microenvironment (TME) plays a pivotal role in immunotherapy resistance, previous studies mainly focused on immune cells, neglecting stromal components like pericytes-creating a critical knowledge gap in understanding AM's therapeutic refractoriness.

METHODS

We integrated multiple single-cell transcriptomic datasets from 31 acral melanoma, 13 cutaneous melanoma and 35 normal skin samples. Comprehensive bioinformatics analyses including cell type annotation, differential expression, gene functional enrichment, and cell-cell interaction analysis, were performed to delineate the tumor microenvironment differences between acral and cutaneous melanoma. Key findings were validated using spatial transcriptomics, bulk RNA-seq datasets, and functional assays including qPCR and western blot.

RESULTS

AM had a more immunosuppressive TME, enriched in collagen-secreting RGS5 + /COL3A1 + pericytes that co-localized with KDR + /PODXL + endothelial cells, associated with vascular abnormalities and hypoxia. These collagen-secreting RGS5 + /COL3A1 + pericytes (enriched in AM) were significantly negatively correlated with the infiltration ratio of CD8 + tumor-infiltrating lymphocytes (TILs); moreover, in immunotherapy cohorts, high expression of the collagen-secreting pericyte marker RGS5 was associated with poorer response to immune checkpoint blockade (ICB) treatment. We also identified a hypoxia-related NECTIN2-TIGIT immunosuppressive axis: hypoxia upregulated NECTIN2 on multiple cells, interacting with TIGIT on T cells to potentially exacerbate dysfunction.

CONCLUSIONS

This study provides insights into vascular-stromal features associated with immunotherapy resistance in AM, highlighting RGS5 + /COL3A1 + pericytes and the NECTIN2-TIGIT axis as targets, and guides development of effective combination immunotherapies for AM.

论文信息

作者
Dong Q、Zhang Y、He F、Sun A
第一作者单位
State Key Laboratory of Medical Proteomics, National Center for Protein Sciences (Beijing), Research Unit of Proteomics Driven Cancer Precision Medicine (Chinese Academy of Medical Sciences), Beijing, 102206, China.China
通讯作者单位
State Key Laboratory of Medical Proteomics, National Center for Protein Sciences (Beijing), Research Unit of Proteomics Driven Cancer Precision Medicine (Chinese Academy of Medical Sciences), Beijing, 102206, China. sunah620@126.com.China
文献类型
非美国政府资助研究
期刊
Journal of translational medicine2026 May 7
原文标识
PubMed 42098765　·　DOI 10.1186/s12967-026-08201-2

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