PO.TB10.16 · 肿瘤生物学
CCL20高表达的趋化因子程序在胃癌中定义了一个CCR6⁺免疫-髓系微环境
A CCL20-high chemokine program defines a CCR6⁺ immune-myeloid niche in gastric cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
引言：胃癌仍是全球癌症死亡的主要原因之一，其特点是临床进程侵袭性强，肿瘤微环境高度免疫抑制，治疗选择有限。趋化因子信号已成为胃肿瘤进展的重要调控因子，在这些通路中，CCL20-CCR6轴是上皮-间质转化、侵袭和转移的公认驱动因素，并与患者不良生存相关。然而，在胃肿瘤内产生高水平CCL20的上游信号，以及响应该信号的特定CCR6⁺免疫区室，仍知之甚少。理解该轴的来源及下游信号传导，可能为胃癌提供新的治疗选择。在此，我们鉴定出一种此前未被认识的CCL20高表达趋化因子特征，以及胃癌中一个受动态调控的CCR6⁺免疫和髓系微环境。
方法：
对小鼠胃癌细胞系进行趋化因子谱分析，对分离自胃癌临床前模型的胃肿瘤进行多重免疫组织化学，并与人胃癌单细胞RNA-seq整合，证实了胃癌细胞表达CCL20，以及胃肿瘤微环境中髓系和B系细胞簇表达CCR6。
结果：
胃癌小鼠类器官表现出独特的趋化因子特征，以高表达CCL20以及CCL22和M-CSF为标志。共聚焦成像证实胃肿瘤和类器官内存在丰富的CCL20蛋白。对TCGA胃腺癌数据的分析表明，高CCR6表达与总生存期降低相关。多重免疫组织化学显示，大量CCR6阳性CD11c⁺MHCII⁺免疫细胞浸润至胃癌肿瘤微环境中，包括B220⁺浆细胞样树突状细胞（pDC样）亚群。pDC样细胞随肿瘤负荷增加而增多，并受抗PD-1和5-氟尿嘧啶治疗的调控，表明CCR6⁺髓系亚群受到动态调控。人胃癌单细胞RNA-seq数据集鉴定出髓系细胞簇上的CCR6表达，这些细胞能够通过CCR6受体响应CCL20。
结论：
这些发现定义了胃癌中一个此前未被认识的CCL20高表达、CCR6⁺免疫-髓系细胞群，为驱动免疫细胞募集至胃癌肿瘤微环境的趋化因子来源提供了洞见。靶向该轴可能揭示胃癌进展中可干预的脆弱性。
查看英文原文 English abstract
Introduction: Gastric cancer remains one of the leading causes of cancer mortality worldwide and is characterized by an aggressive clinical course and a profoundly immunosuppressive tumor microenvironment with limited therapeutic options. Chemokine signaling has emerged as an important regulator of gastric tumor progression, and among these pathways, the CCL20-CCR6 axis is a validated driver of epithelial to mesenchymal transition, invasion, and metastasis, and is associated with poor patient survival. However, the upstream signals that generate high levels of CCL20 within gastric tumors, and the specific CCR6⁺ immune compartment that respond to this signal remain poorly understood. Understanding the source and downstream signaling for this axis may offer novel therapeutic options for gastric cancer. Here, we identify a previously unrecognized CCL20 high chemokine signature and a dynamically regulated CCR6⁺ immune and myeloid niche in gastric cancer.
Methods:
Chemokine profiling of murine gastric cancer cell lines, multiplex immunohistochemistry of gastric tumors isolated from preclinical models of gastric cancer, and integration with human gastric single-cell RNA-seq confirmed CCL20 expression by gastric cancer cells and CCR6 expression in myeloid and B lineage clusters in the gastric tumor microenvironment.
Results:
Gastric cancer murine organoids exhibited a distinct chemokine signature marked by high CCL20 together with CCL22 and M-CSF. Confocal imaging confirmed abundant CCL20 protein within gastric tumors and organoids. Analysis of TCGA stomach adenocarcinoma data demonstrated that high CCR6 expression correlates with reduced overall survival. Multiplex immunohistochemistry revealed that substantial CCR6 positive CD11c⁺ MHCII⁺ immune cells infiltrate into the gastric cancer tumor microenvironment, including B220⁺ plasmacytoid DC-like (pDC-like) subset. pDC-like cells increased with tumor burden and was modulated by anti-PD-1 and 5-fluorouracil treatment, indicating dynamic regulation of CCR6⁺ myeloid subsets. Human gastric single-cell RNA-seq datasets identified CCR6 expression on myeloid clusters capable of responding to CCL20 through the CCR6 receptor.
Conclusions:
These findings define a previously unrecognized CCL20-high, CCR6⁺ immune-myeloid population in gastric cancer that offers insight into the source of chemokines that drive recruitment of immune cells into the gastric cancer tumor microenvironment. Targeting this axis may reveal actionable vulnerabilities in gastric cancer progression.
利益披露 Disclosure
K. Ozuner, None..
J. Kim, None.