PO.TB10.11 · 肿瘤生物学
SFRP4+癌症相关成纤维细胞驱动肝细胞癌中IL-6/STAT3介导的EMT和免疫抑制性肿瘤微环境
SFRP4+ cancer-associated fibroblasts drive IL-6/STAT3-mediated EMT and immunosuppressive tumor microenvironment in hepatocellular carcinoma
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摘要 Abstract
中文摘要
背景：分泌型卷曲相关蛋白4（SFRP4）是一种Wnt调节因子，SFRP4⁺成纤维细胞亚群近期已在多种癌症类型中被鉴定。然而，关于SFRP4⁺癌症相关成纤维细胞（CAFs）在肝细胞癌（HCC）中直接介导免疫抑制和治疗耐药的证据仍然有限。本研究旨在阐明SFRP4⁺CAFs如何重编程肿瘤微环境（TME）以驱动HCC中的免疫抑制和治疗耐药。
方法：对来自HCC患者的8对匹配的CAF与癌旁成纤维细胞（PAF）进行全转录组测序（WTS），并整合5个公开可用的HCC数据集以鉴定候选基因。使用GepLiver数据库中的CellChat分析来分析TME中的细胞间相互作用。通过使用原代CAFs和HCC细胞系的体外共培养实验，以及体内异种移植和人源化小鼠模型进行功能验证。进一步对阿替利珠单抗-贝伐珠单抗（Atezo/Beva）应答组和无应答组的肿瘤进行转录组分析，以评估临床相关性。
结果：SFRP4⁺CAFs表现出以IL6和NECTIN2表达显著诱导为特征的炎性表型。HCC细胞与SFRP4⁺CAFs共培养增加磷酸化STAT3和CD44表达，增强增殖、侵袭和干性，而这些效应在SFRP4敲低后被消除。在免疫层面，SFRP4⁺CAFs通过NECTIN-TIGIT相互作用促进调节性T细胞（Treg）浸润，并诱导M2巨噬细胞极化，建立免疫抑制性微环境。
在人源化小鼠模型中，基于富集评分分析，与SFRP4⁺CAFs共植入的肿瘤显示Treg浸润和M2极化增加。临床上，Atezo/Beva无应答肿瘤表现出SFRP4、IL6-STAT3/CD44和NECTIN-TIGIT通路的上调，并伴有CD8A和GZMA表达降低。
结论：SFRP4⁺CAFs通过IL6-STAT3/CD44信号、NECTIN-TIGIT介导的Treg招募和M2巨噬细胞极化，协调一个多方面的促肿瘤程序。高SFRP4表达与细胞毒性免疫受损及对Atezo/Beva治疗的不良应答相关。靶向SFRP4⁺CAFs可能代表一种克服肝癌中间质介导免疫耐药的有前景的治疗策略。
查看英文原文 English abstract
Background: Secreted frizzled-related protein 4 (SFRP4) is a Wnt modulator, and SFRP4⁺ fibroblast subsets have recently been identified across various cancer types. However, evidence that SFRP4⁺ cancer-associated fibroblasts (CAFs) directly mediate immunosuppression and therapeutic resistance in hepatocellular carcinoma (HCC) remains limited. This study aimed to elucidate how SFRP4⁺ CAFs reprogram the tumor microenvironment (TME) to drive immune suppression and treatment resistance in HCC.
Methods: Whole-transcriptome sequencing (WTS) was performed on eight matched CAF and paracancer fibroblast (PAF) pairs from HCC patients, and five publicly available HCC datasets were integrated to identify candidate genes. Cell-cell interactions in the TME were analyzed using CellChat analysis in the GepLiver database. Functional validation was conducted through in vitro coculture assays using primary CAFs and HCC cell lines, as well as in vivo xenograft and humanized mouse models. Transcriptomic profiling of tumors from atezolizumab-bevacizumab (Atezo/Beva) responder and non-responder groups was further performed to assess clinical relevance.
Results: SFRP4⁺ CAFs exhibited an inflammatory phenotype characterized by marked induction of IL6 and NECTIN2 expression. Coculture of HCC cells with SFRP4⁺ CAFs increased phosphorylated STAT3 and CD44 expression, enhancing proliferation, invasion, and stemness, while these effects were abrogated by SFRP4 knockdown. In the immune compartment, SFRP4⁺ CAFs promoted regulatory T-cell (Treg) infiltration via NECTIN-TIGIT interactions and induced M2 macrophage polarization, establishing an immunosuppressive milieu.
In the humanized mouse model, tumors co-implanted with SFRP4⁺ CAFs showed increased Treg infiltration and M2 polarization based on enrichment score analysis. Clinically, Atezo/Beva non-responder tumors exhibited upregulation of SFRP4, IL6-STAT3/CD44, and NECTIN-TIGIT pathways, accompanied by reduced CD8A and GZMA expression.
Conclusions: SFRP4⁺ CAFs orchestrate a multifaceted pro-tumor program through IL6-STAT3/CD44 signaling, NECTIN-TIGIT-mediated Treg recruitment, and M2 macrophage polarization. High SFRP4 expression correlates with impaired cytotoxic immunity and poor response to Atezo/Beva therapy in HCC. Targeting SFRP4⁺ CAFs may represent a promising therapeutic strategy to overcome stromal-mediated immune resistance in liver cancer.
利益披露 Disclosure
H. Cho, None..
S. Kim, None..
H. Ahn, None..
M. Kwon, None..
M. Park, None.