Single-cell profiling of human CD127(+) innate lymphoid cells reveals diverse immune phenotypes in hepatocellular carcinoma.
Single-cell profiling of human CD127(+) innate lymphoid cells reveals diverse immune phenotypes in hepatocellular carcinoma.
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DOI：
10.1002/hep.32444
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发表时间：
2022-10
期刊：
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先天淋巴细胞（ILC）是组织驻留淋巴细胞，在细胞因子介导的体内平衡和炎症调节中发挥着关键作用。然而，它们的免疫表型特征与 HCC 之间的关系在很大程度上仍未被探索。我们对来自人类 HCC 患者的分选肝 ILC 细胞进行了单细胞 RNA 测序分析，并使用流式细胞术、多重免疫荧光染色和功能实验进行了验证。此外，我们应用选择策略来富集 HCC 样本中的 ILC 群体，以研究 B 细胞对诱导性 T 细胞共刺激物 (ICOS)+ ILC2 细胞免疫反应的影响。 ILC 的失调通过 HCC 中细胞数量或子集比例的变化来体现。 3433 个 ILC 的 7 个亚群被鉴定出具有独特的特性，其中 ICOS+ ILC2a 在 HCC 中优先富集，并与不良预后相关。从机制上讲，我们报告 B 细胞，特别是静息幼稚 B 细胞，具有以前未被识别的功能，该功能参与 ILC2 细胞的炎症分化。 B 细胞衍生的 ICOSL 信号传导通过增加 ICOS+ ILC2a 细胞中 IL-13 的产生而加剧炎症。热休克蛋白70（HSP70）基因热休克蛋白家族A成员1A（HSPA1A）和热休克蛋白家族A成员1B（HSPA1B）在晚期HCC的ILC2中高表达，靶向ILC2中的ICOS及其下游效应子HSP70可抑制肿瘤生长并重塑免疫抑制肿瘤微环境。这一深入的理解揭示了 B 细胞驱动的先天 2 型炎症，并为 HCC 免疫治疗提供了潜在的策略。
Innate lymphoid cells (ILCs) are tissue‐resident lymphocytes that play critical roles in cytokine‐mediated regulation of homeostasis and inflammation. However, relationships between their immune phenotypic characteristics and HCC remain largely unexplored. We performed single‐cell RNA sequencing analysis on sorted hepatic ILC cells from human patients with HCC and validated using flow cytometry, multiplex immunofluorescence staining, and functional experiments. Moreover, we applied selection strategies to enrich ILC populations in HCC samples to investigate the effects of B cells on the immune reaction of inducible T cell costimulator (ICOS)+ ILC2 cells. Dysregulation of ILCs was manifested by the changes in cell numbers or subset proportions in HCC. Seven subsets of 3433 ILCs were identified with unique properties, of which ICOS+ ILC2a were preferentially enriched in HCC and correlated with poor prognosis. Mechanistically, we report that B cells, particularly resting naïve B cells, have a previously unrecognized function that is involved in inflammatory differentiation of ILC2 cells. B cell–derived ICOSL signaling was responsible for exacerbating inflammation through the increased production of IL‐13 in ICOS+ ILC2a cells. Heat shock protein 70 (HSP70) genes Heat Shock Protein Family A Member 1A (HSPA1A) and Heat Shock Protein Family A Member 1B (HSPA1B) were highly expressed in ILC2s in late‐stage HCC, and targeting to ICOS and its downstream effector HSP70 in ILC2s suppressed tumor growth and remodeled the immunosuppressive tumor microenvironment. This in‐depth understanding sheds light on B cell‐driven innate type 2 inflammation and provides a potential strategy for HCC immunotherapy.
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DOI：
10.1002/iid3.161
发表时间：
2017-09
期刊：
Immunity, inflammation and disease
影响因子：
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作者：
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10.1016/j.jaci.2018.03.007
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2019-01
期刊：
The Journal of allergy and clinical immunology
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Derre, Laurent
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Newell EW
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Korangy F