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CCL18＋肿瘤相关巨噬细胞通过表达PD-L1及TGF-β诱导胃癌免疫逃逸

CCL18＋tumor-associated macrophages induce immune escape by expressing PD-L1 and TGF-β

    摘要
  • 摘要:
    目的 探讨CC趋化因子配体 18（CC chemokine ligand-18, CCL18）阳性肿瘤相关巨噬细胞在胃癌免疫逃逸中的作用及其对肿瘤微环境的影响。
    方法 纳入复旦大学附属中山医院的3个胃癌患者队列（根治性手术队列449例，姑息性治疗队列46例，流式细胞分析队列48例），以及癌症基因组图谱（The Cancer Genome Atlas, TCGA）胃癌数据库的336例患者。CCL18＋肿瘤相关巨噬细胞基因特征从TCGA数据库获取，根据基因特征分析TCGA队列差异基因表达。通过免疫荧光检测两治疗队列患者组织芯片中CCL18＋肿瘤相关巨噬细胞浸润情况。分析CCL18＋肿瘤相关巨噬细胞与临床结局及相关基因表达之间的关联。利用肿瘤组织来源的单细胞悬液，通过流式细胞术评估CCL18＋肿瘤相关巨噬细胞免疫表型；通过体外培养评估阻断CCL18在胃癌中的潜在治疗效果。
    结果 根治性手术队列中，CCL18＋肿瘤相关巨噬细胞高浸润组总生存时间、无病生存时间短于低浸润组（P＜0.01）；姑息性治疗队列中，CCL18＋肿瘤相关巨噬细胞高浸润组疾病无进展时间短于低浸润组（P＝0.015）。CCL18＋肿瘤相关巨噬细胞高浸润组肿瘤组织耗竭型CD8＋T细胞比例高于低浸润组（P＜0.001）。TCGA队列中，CCL18＋肿瘤相关巨噬细胞基因特征高表达胃癌组织程序性死亡配体1（programmed death-ligand 1, PD-L1）和转化生长因子β（transforming growth factor-β, TGF-β）表达水平高于低表达胃癌组织（P＜0.001）。CCL18＋肿瘤相关巨噬细胞PD-L1和TGF-β表达水平高于CCL18－肿瘤相关巨噬细胞（P＜0.05）；加入CCL18抗体后，肿瘤组织中杀伤性CD8＋T细胞及凋亡（Annexin Ⅴ＋）上皮细胞比例升高（P＜0.05），增殖（Ki67＋）上皮细胞比例降低（P＜0.001）。
    结论 CCL18＋肿瘤相关巨噬细胞浸润水平与胃癌患者预后相关，可能通过表达PD-L1和TGF-β促进胃癌免疫抑制微环境形成，阻断CCL18可能是胃癌治疗新方向。

     

    Abstract:
    Objective To explore the role of CC chemokine ligand-18 (CCL18) positive tumor-associated macrophages in immune escape of gastric cancer and their impact on the tumor microenvironment.
    Methods Three gastric cancer patient cohorts were included in Zhongshan Hospital, Fudan University (449 cases in the radical surgery cohort, 46 cases in the palliative treatment cohort, and 48 cases in the flow cytometry analysis cohort), and one group of patients from The Cancer Genome Atlas (TCGA) database were included. The CCL18+ tumor-associated macrophage gene signature was obtained from the TCGA database, and differential gene expression in the TCGA cohort was analyzed based on this signature. Immunofluorescence was used to assess the infiltration of CCL18+ tumor-associated macrophages in tissue microarrays of patients from two treatment cohorts. The association between CCL18+ tumor-associated macrophages and clinical outcomes as well as related gene expression was examined. Using single-cell suspensions derived from tumor tissues, flow cytometry was employed to evaluate the immunophenotype of CCL18+ tumor-associated macrophages; the potential therapeutic effects of blocking CCL18 in gastric cancer were assessed through in vitro culture.
    Results In curative surgery cohort, patients with high infiltration of CCL18＋tumor-associated macrophages had shorter overall survival and disease-free survival compared to those with low infiltration (P＜0.01). In palliative cohort, patients with high infiltration of CCL18＋tumor-associated macrophages exhibited shorter progression-free survival compared to those with low infiltration (P＝0.015). The proportion of exhausted CD8＋T cells was significantly increased in the cancer tissues with high infiltration of CCL18＋tumor-associated macrophages compared to those with low infiltration (P＜0.001). Tumors with high CCL18＋tumor-associated macrophages gene signature expressed significantly higher level of programmed death-ligand 1 (PD-L1) and transforming growth factor-β (TGF-β）than those with low CCL18＋tumor-associated macrophages gene signature in TCGA queue (P＜0.001). The expression levels of PD-L1 and TGF-β were higher in CCL18＋tumor-associated macrophages than those in CCL18－tumor-associated macrophages (P＜0.05). After CCL18 intervention, the proportions of cytotoxic CD8+ T cells and apoptotic epithelial cells (Annexin Ⅴ＋) were increased (P＜0.05), while the proportion of proliferating epithelial cells (Ki67＋) was decreased (P＜0.001).
    Conclusion CCL18＋tumor-associated macrophages infiltration is associated with prognoses in patients with gastric cancer, and might promote an immunosuppressive microenvironment in gastric cancer by expressing PD-L1 and TGF-β, and blockade of CCL18 might be a new direction for gastric cancer treatment.

     

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