PO.TB10.11 · 肿瘤生物学
在胃癌中鉴定出一种免疫激活和肿瘤抑制型的癌症相关成纤维细胞亚型
An immune-activating and tumor-suppressive subtype of cancer-associated fibroblasts identified in gastric cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
肿瘤微环境（TME）是晚期胃癌（GC）进展和治疗耐药的关键决定因素，其中癌症相关成纤维细胞（CAFs）是一个核心组成部分。尽管促肿瘤型 CAFs 已被广泛表征，但肿瘤抑制型 CAF 亚群的身份和调控机制仍不清楚。为解决这一问题，我们分析了源自胃癌（GC）样本的单细胞 RNA 测序（scRNA-seq）数据集，鉴定出以高表达抗肿瘤相关基因（如 CXCL10 和 ASPN）为特征的成纤维细胞亚簇。进一步分析揭示，编码 Chemerin 的 RARRES2 是定义该 CAF 亚群的标志基因之一。Chemerin 是一种具有趋化和代谢功能的多功能蛋白。越来越多的证据表明，Chemerin 介导多种免疫细胞类型的募集，从而影响免疫监视和炎症过程。然而，其在肿瘤微环境中的确切作用尚未被完全阐明。在功能上，重组 Chemerin 在体外可强效诱导 CD8+ T 细胞迁移。通过共培养模型和机制解析，我们证明肿瘤细胞通过激活 Jag1-Notch2-HDAC5 信号轴，主动抑制 CAFs 中 RARRES2/Chemerin 的表达，导致表观遗传沉默。关键的是，在体内 CAF 特异性过表达 RARRES2 足以减弱肿瘤生长并显著增强 CD8+ T 细胞向肿瘤的募集。我们的发现明确鉴定 Chemerin+ CAFs 是一个关键的基质亚群，通过募集细胞毒性 T 细胞来协调抗肿瘤免疫。此外，我们揭示了一种动态且可治疗靶向的串扰，其中肿瘤细胞通过 Jag1-Notch2-HDAC5 信号颠覆这一基质防御机制，从而鉴定出 GC 中一条新的免疫逃逸通路。
查看英文原文 English abstract
The tumor microenvironment (TME) is a critical determinant of progression and therapy resistance in advanced gastric cancer (GC), with cancer-associated fibroblasts (CAFs) being a key component. While protumorigenic CAFs have been extensively characterized, the identity and regulatory mechanisms of tumor-suppressive CAF subsets remain elusive. To address this, we analyzed single-cell RNA sequencing (scRNA-seq) datasets derived from gastric cancer (GC) samples and identified fibroblast subclusters characterized by high expression of antitumor-associated genes such as CXCL10 and ASPN. Further analysis revealed that RARRES2, encoding Chemerin, was one of the signature genes defining this CAF subpopulation. Chemerin is a multifunctional protein exhibiting chemotactic and metabolic functions. Accumulating evidence indicates that Chemerin mediates the recruitment of multiple immune cell types, thereby influencing immune surveillance and inflammatory processes. However, its precise roles within the tumor microenvironment have yet to be fully elucidated. Functionally, recombinant Chemerin potently induced CD8+ T cell migration in vitro. Through co-culture models and mechanistic dissection, we demonstrated that tumor cells actively suppress RARRES2/Chemerin expression in CAFs by activating the Jag1-Notch2-HDAC5 signaling axis, leading to epigenetic silencing. Crucially, CAF-specific overexpression of RARRES2 in vivo was sufficient to attenuate tumor growth and profoundly augment the recruitment of CD8+ T cells into tumors. Our findings definitively identify Chemerin+ CAFs as a pivotal stromal subset that orchestrates antitumor immunity by recruiting cytotoxic T cells. Furthermore, we unveil a dynamic and therapeutically targetable crosstalk wherein tumor cells subvert this stromal defense mechanism via Jag1-Notch2-HDAC5 signaling, thereby identifying a novel immune-evasion pathway in GC.
利益披露 Disclosure
H. Wang, None.