Inhaled IL-10 Suppresses Lung Tumorigenesis via Abrogation of Inflammatory Macrophage-Th17 Cell Axis
Inhaled IL-10 Suppresses Lung Tumorigenesis via Abrogation of Inflammatory Macrophage-Th17 Cell Axis
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DOI：
10.4049/jimmunol.1800141
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发表时间：
2018-11-01
影响因子：
4.4
通讯作者：
Egilmez, Nejat K.
中科院分区：
文献类型：
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作者：
Li, Qingsheng;Anderson, Charles D.;Egilmez, Nejat K.
在 LSL-K-ras(G12D) 小鼠肺癌模型中，气管内施用新型 IL-10 制剂可抑制 IL-17 驱动的 CD4(+) T 细胞依赖性肿瘤发生。对肺淋巴细胞群的分析表明，IL-10 的抗肿瘤活性与 Th17 细胞流行率下降 5 倍以及同时抑制炎症性 M1 样巨噬细胞活性相关。进一步的表型表征表明，巨噬细胞和树突状细胞（而非 Th17 细胞）在细胞表面表达 IL-10RA，其中 CD11b(+)F4/80(+)CX3CR1(+) 间质巨噬细胞代表主要的 IL-10RA(+) 亚群。与这些观察结果一致，用IL-10对分选的CD4(+)T细胞进行体外刺激并不影响它们产生IL-17的能力，而对纯化的间质巨噬细胞进行类似的处理导致了M1到M2表型的显着转变。重要的是，在体外共培养测定中，用IL-10预处理巨噬细胞（但不是CD4（+）T细胞）可有效抑制CD4（+）T细胞IL-17的产生，表明IL-10主要通过其对巨噬细胞的上游作用抑制Th17细胞活性。为了支持这一观点，体内巨噬细胞耗竭导致 Th17 细胞数量减少 5 倍，同时肿瘤负荷减少 6 倍。总的来说，这些数据表明，在 LSL-K-ras(G12D) 小鼠肺癌模型中，炎症巨噬细胞-Th17 细胞轴对于肿瘤发生至关重要，而 IL-10 主要通过直接作用于前者来阻断这一过程。吸入 IL-10 制剂可用于预防高危患者的肺癌。
Intratracheal administration of a novel IL-10 formulation suppressed IL-17-driven, CD4(+) T cell-dependent tumorigenesis in the LSL-K-ras(G12D) murine lung cancer model. Analysis of lung lymphocyte populations demonstrated that antitumor activity of IL-10 was associated with a 5-fold decline in Th17 cell prevalence and a concurrent suppression of inflammatory M1-like macrophage activity. Further phenotypic characterization revealed that macrophages and dendritic cells, but not Th17 cells, expressed IL-10RA on the cell surface with the CD11b(+)F4/80(+)CX3CR1(+) interstitial macrophages representing the dominant IL-10RA(+) subset. Consistent with these observations, in vitro stimulation of sorted CD4(+) T cells with IL-10 did not affect their ability to produce IL-17, whereas similar treatment of purified interstitial macrophages resulted in a dramatic M1 to M2 phenotypic switch. Importantly, preconditioning of macrophages (but not of CD4(+) T cells) with IL-10 led to potent suppression of CD4(+) T cell IL-17 production in an in vitro coculture assay, suggesting that IL-10 suppressed Th17 cell activity primarily via its upstream effects on macrophages. In support of this notion, in vivo macrophage depletion resulted in a 5-fold decline in Th17 cell numbers and a concurrent 6-fold reduction in tumor burden. Collectively, these data demonstrate that in the LSL-K-ras(G12D) murine lung cancer model, inflammatory macrophage-Th17 cell axis is critical to tumorigenesis and that IL-10 blocks this process primarily via a direct effect on the former. Inhaled IL-10 formulations may be of use in prophylaxis against lung cancer in high-risk patients.