Mannewitz Mareike, Kolben Thomas, Perleberg Carolin, Meister Sarah, Hahn Laura, Mitter Sophie, Schmoeckel Elisa, Mahner Sven, Corradini Stefanie, Trillsch Fabian, Kessler Mirjana, Jeschke Udo, Beyer Susanne
Department of Obstetrics and Gynecology, University Hospital, LMU Munich, Munich, Germany.
Department of Obstetrics and Gynecology, University Hospital, LMU Munich, Munich, Germany.
Transl Oncol. 2024 Dec;50:102116. doi: 10.1016/j.tranon.2024.102116. Epub 2024 Sep 3.
The chemokine CCL22 is recognized for recruiting immunosuppressive regulatory T-cells (Treg) that contribute to disease progression in various tumor entities helping them to evade the host immune response. Our study aims to identify the expressing cell types and to evaluate the prognostic significance of CCL22 secretion and its association with Treg invasion in endometrial cancer (EC), an immunogenic cancer.
Specimens from 275 patients with EC and 28 healthy controls were screened immunohistochemically for CCL22. Immunofluorescence double-staining for CCL22 and different immune cell markers was performed. In vitro regulation of CCL22-expression was examined in EC cell lines (Ishikawa+, RL95-2) and human PBMCs in coculture settings via qPCR and ELISA.
Elevated CCL22 staining in tumor cells and CCL22-positive M1-macrophages in tumordistant areas were significantly associated with increased overall survival (OS). Conversely, high, secretory-appearing staining in the peritumoral and intratumoral stroma correlated with reduced OS. Although the analysis of the in vitro coculture model of epithelial tumor- and immune cells revealed PBMCs as the primary source of CCL22, we could confirm expression of the chemokine also in the EC epithelial cells.
Our study suggests that CCL22 in EC is associated with OS, dependent on its location and the cell type producing it. Intracellular upregulation and extracellular secretion must be considered separately when investigating CCL22 expressing cell types in EC. These results may provide evidence for CCL22-mediated Treg recruitment in EC as a potential future therapeutic target.
趋化因子CCL22可募集免疫抑制性调节性T细胞（Treg），这些细胞会促进多种肿瘤实体的疾病进展，帮助肿瘤逃避宿主免疫反应。我们的研究旨在确定CCL22的表达细胞类型，并评估CCL22分泌在子宫内膜癌（EC，一种具有免疫原性的癌症）中的预后意义及其与Treg浸润的关系。
对275例EC患者和28例健康对照的标本进行CCL22免疫组化筛查。对CCL22和不同免疫细胞标志物进行免疫荧光双染色。通过qPCR和ELISA在共培养环境中检测EC细胞系（Ishikawa+、RL95-2）和人外周血单核细胞（PBMC）中CCL22表达的体外调节情况。
肿瘤细胞中CCL22染色升高以及肿瘤远处区域CCL22阳性的M1巨噬细胞与总生存期（OS）延长显著相关。相反，肿瘤周围和肿瘤内基质中高的、呈分泌样的染色与OS降低相关。尽管对上皮肿瘤细胞和免疫细胞的体外共培养模型分析显示PBMC是CCL22的主要来源，但我们也证实了趋化因子在EC上皮细胞中也有表达。
我们的研究表明，EC中的CCL22与OS相关，这取决于其位置和产生它的细胞类型。在研究EC中CCL22表达细胞类型时，必须分别考虑细胞内上调和细胞外分泌情况。这些结果可能为EC中CCL22介导的Treg募集作为潜在的未来治疗靶点提供证据。
