AIM Tumour-associated macrophages (TAMs) are prominent immune cells infiltrating in solid tumours with phenotypic and functional heterogeneity. However, the clinical significance of heterogeneous subtypes of TAMs in gastric cancer still remains obscure. Here, we aimed to explore the clinical significance of TAMs expressing dendritic cell-specific intercellular adhesion molecule 3-grabbing non-integrin (DC-SIGN) and its relevance with immune contexture in gastric cancer. METHODS We selected 453 formalin-fixed and paraffin-embedded samples and 51 fresh tissue specimens of patients with gastric cancer from Zhongshan Hospital. The association of DC-SIGN+ macrophages with clinicopathological parameters, overall survival (OS) and responsiveness to fluorouracil-based adjuvant chemotherapy (ACT) was inspected. Immunohistochemistry (IHC) and flow cytometry (FCM) were applied to characterize immune cells in gastric cancer. RESULTS We demonstrated that high intratumoral DC-SIGN+ macrophages infiltration predicted poor OS and inferior therapeutic responsiveness to fluorouracil-based ACT in patients with gastric cancer. Furthermore, higher infiltration of DC-SIGN+ macrophages indicated an increased number of Foxp3+ regulatory T cells (Tregs), CD8+ T cells and a higher ratio of Foxp3+/CD8+ within the tumour microenvironment (TME). In addition, CD8+ T cells in DC-SIGN+ macrophages high subgroup were functionally impaired, showing decreased interferon-γ (IFN-γ), granzyme B (GZMB) and perforin production yet elevated programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) expression. CONCLUSIONS DC-SIGN+ macrophages were associated with immunoinvasive TME and indicated poor prognosis and inferior therapeutic responsiveness to fluorouracil-based ACT. DC-SIGN+ macrophages might be an independent prognosticator and a potential immunotherapeutic target for gastric cancer.

中文翻译：

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胃癌中肿瘤内树突状细胞特异性细胞间粘附分子3抢夺非整联蛋白阳性巨噬细胞与免疫逃逸相关的不良临床结果。

AIM肿瘤相关巨噬细胞（TAM）是浸润在具有表型和功能异质性的实体瘤中的重要免疫细胞。但是，TAMs异质亚型在胃癌中的临床意义仍然不清楚。在这里，我们旨在探讨TAMs表达树突状细胞特异性细胞间粘附分子3劫掠非整联蛋白（DC-SIGN）的临床意义及其与胃癌免疫情况的相关性。方法我们从中山医院选择了453例福尔马林固定和石蜡包埋的样本以及51例新鲜的胃癌组织样本。检查了DC-SIGN +巨噬细胞与临床病理参数，总生存期（OS）和对基于氟尿嘧啶的辅助化疗（ACT）的反应性之间的关系。免疫组织化学（IHC）和流式细胞仪（FCM）被用于表征胃癌中的免疫细胞。结果我们证明，胃癌患者中高的肿瘤内DC-SIGN +巨噬细胞浸润预示着OS差，对基于氟尿嘧啶的ACT的治疗反应较差。此外，DC-SIGN +巨噬细胞的更高浸润表明在肿瘤微环境（TME）内Foxp3 +调节性T细胞（Tregs），CD8 + T细胞的数目增加，并且Foxp3 + / CD8 +的比率更高。此外，DC-SIGN +巨噬细胞高亚组的CD8 + T细胞功能受损，表现出干扰素-γ（IFN-γ），颗粒酶B（GZMB）和穿孔素生成减少，但程序性细胞死亡蛋白1（PD-1）和细胞毒性增加。 T淋巴细胞相关蛋白4（CTLA-4）的表达。结论DC-SIGN +巨噬细胞与免疫浸润性TME相关，预后差，对基于氟尿嘧啶的ACT的治疗反应较差。DC-SIGN +巨噬细胞可能是胃癌的独立预后因子和潜在的免疫治疗靶标。