Department of Gastrointestinal Surgery, Shandong Provincial Third Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
Department of Oncology, Changhai Hospital, Naval Medical University, Shanghai, China.
Front Immunol. 2024 Oct 25;15:1446613. doi: 10.3389/fimmu.2024.1446613. eCollection 2024.
Gastric cancer (GC) remains a global health threat due to frequent treatment failures caused by primary or acquired resistance. Although cancer-associated fibroblasts (CAFs) have been implicated in this process, it is still unclear which specific subtype(s) of CAFs hinder T-cell infiltration and promote resistance to immunotherapy.
We analyzed the GC fibroblast atlas in detail by combining 63,955 single cells from 14 scRNA-seq datasets. We also performed RNA-seq data in a local GC cohort and examined 13 bulk RNA-seq datasets to understand the biological and clinical roles of different CAF subsets. Additionally, we conducted experiments to study the role of specific proteins in GC development.
We identified a total of 17 fibroblast subsets in gastric cancer, nine of which did not fit into the existing CAFs classification. These subsets exhibited significant heterogeneity in distribution and biological characteristics (metabolism, cell-cell interactions, differentiation state), as well as clinical functions such as prognosis and response to immunotherapy. In particular, cluster 6 stood out for its high expression of MFAP5, CFD, and PI16; it was found to be negatively associated with both overall survival and response to immunotherapy in GC. This association was linked to an immunosuppressive microenvironment characterized by an increase in M2 macrophages but higher levels of T cell dysfunction and exclusion-a feature shared by tumors expressing MFAP5. Furthermore, the addition of human recombinant MFAP5 promoted proliferation and migration of HGC-27 cells by inducing the MFAP5/NOTCH1/HEY1 signaling pathway.
We introduce a high-resolution GC fibroblast atlas. The 17 identified fibroblast clusters provide valuable opportunities for gaining deeper biological insights into the relationship between fibroblasts and GC development. Particularly, cluster 6 and its specific marker MFAP5 could serve as prognostic factors in GC and form a foundation for personalized therapeutic combinations to address primary resistance to ICIs.
由于原发性或获得性耐药导致治疗失败频繁，胃癌（GC）仍然是全球健康威胁。尽管癌症相关成纤维细胞（CAFs）已被牵涉到这个过程中，但仍不清楚哪种特定的 CAF 亚群阻碍 T 细胞浸润并促进对免疫疗法的耐药性。
我们通过结合来自 14 个 scRNA-seq 数据集的 63955 个单细胞，详细分析了 GC 成纤维细胞图谱。我们还在一个本地 GC 队列中进行了 RNA-seq 数据，并检查了 13 个批量 RNA-seq 数据集，以了解不同 CAF 亚群的生物学和临床作用。此外，我们进行了实验来研究特定蛋白质在 GC 发展中的作用。
我们总共在胃癌中鉴定出 17 种成纤维细胞亚群，其中 9 种不符合现有的 CAFs 分类。这些亚群在分布和生物学特征（代谢、细胞-细胞相互作用、分化状态）以及临床功能（如预后和对免疫疗法的反应）方面表现出显著的异质性。特别是，簇 6 以其高表达 MFAP5、CFD 和 PI16 为特征；研究发现，它与 GC 中的总生存期和对免疫疗法的反应呈负相关。这种相关性与一个免疫抑制的微环境有关，其特征是 M2 巨噬细胞增加，但 T 细胞功能障碍和排斥增加——这是表达 MFAP5 的肿瘤的共同特征。此外，添加人重组 MFAP5 通过诱导 MFAP5/NOTCH1/HEY1 信号通路促进 HGC-27 细胞的增殖和迁移。
我们引入了一个高分辨率的 GC 成纤维细胞图谱。鉴定出的 17 个成纤维细胞簇为深入了解成纤维细胞与 GC 发展之间的关系提供了有价值的机会。特别是，簇 6 及其特定标志物 MFAP5 可以作为 GC 的预后因素，并为解决对 ICI 的原发性耐药的个性化治疗组合奠定基础。
