The ecto-ATPDase CD39 is involved in the acquisition of the immunoregulatory phenotype by M-CSF-macrophages and ovarian cancer tumor-associated macrophages: Regulatory role of IL-27
The ecto-ATPDase CD39 is involved in the acquisition of the immunoregulatory phenotype by M-CSF-macrophages and ovarian cancer tumor-associated macrophages: Regulatory role of IL-27
复制标题
胞外ATP酶CD 39参与M-CSF-巨噬细胞和卵巢癌肿瘤相关巨噬细胞免疫调节表型的获得：IL-27的调节作用
DOI：
10.1080/2162402x.2016.1178025
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发表时间：
2016-01-01
期刊：
影响因子：
7.2
通讯作者：
Tabiasco, Julie
中科院分区：
文献类型：
--
作者：
d'Almeida, Senan M.;Kauffenstein, Gilles;Tabiasco, Julie
肿瘤相关巨噬细胞（TAM）是一种免疫抑制细胞，可以在肿瘤微环境中大量积聚。在卵巢癌患者中，其密度与预后不良相关。控制免疫调节巨噬细胞的产生或分化的靶向介质代表了克服肿瘤相关免疫抑制的治疗挑战。外核苷酸酶CD 39将ATP水解成细胞外腺苷，当通过A2 A腺苷受体进行信号传导时，细胞外腺苷表现出有效的免疫抑制特性。我们在此报告，从卵巢癌患者和体外用M-CSF产生的巨噬细胞中分离的CD 14（+）CD 163（+）TAM与经典活化的巨噬细胞相比，表达高水平的膜外核苷酸酶CD 39。CD 39抑制剂POM-1和腺苷脱氨酶（ADA）降低了CD 14（高）CD 163（高）CD 39（高）巨噬细胞的一些免疫抑制功能，如IL-10分泌。我们确定了细胞因子IL-27，由肿瘤浸润中性粒细胞分泌，位于浸润CD 163（+）巨噬细胞附近，作为CD 39表达的主要变阻器，因此，对巨噬细胞获得免疫调节特性。因此，IL-27的消耗下调了M-CSF-巨噬细胞的CD 39和PD-L1表达以及IL-10分泌。总的来说，这些数据表明，在卵巢癌中由IL-27和CD 115配体驱动的CD 39维持TAM的免疫抑制表型。这项工作带来了新的信息收购免疫抑制特性的肿瘤浸润巨噬细胞。
Tumor-associated macrophages (TAM) are immunosuppressive cells that can massively accumulate in the tumor microenvironment. In patients with ovarian cancer, their density is correlated with poor prognosis. Targeting mediators that control the generation or the differentiation of immunoregulatory macrophages represents a therapeutic challenge to overcome tumor-associated immunosuppression. The ectonucleotidase CD39 hydrolyzes ATP into extracellular adenosine that exhibits potent immunosuppressive properties when signaling through the A2A adenosine receptor. We report here that CD14(+) CD163(+) TAM isolated from ovarian cancer patients and macrophages generated in vitro with M-CSF, express high levels of the membrane ectonucleotidase CD39 compared to classically activated macrophages. The CD39 inhibitor POM-1 and adenosine deaminase (ADA) diminished some of the immunosuppressive functions of CD14(high) CD163(high) CD39(high) macrophages, such as IL-10 secretion. We identified the cytokine IL-27, secreted by tumor-infiltrating neutrophils, located close to infiltrating CD163(+) macrophages, as a major rheostat of CD39 expression and consequently, on the acquisition of immunoregulatory properties by macrophages. Accordingly, the depletion of IL-27 downregulated CD39 and PD-L1 expression as well as IL-10 secretion by M-CSF-macrophages. Collectively, these data suggest that CD39, drived by IL-27 and CD115 ligands in ovarian cancer, maintains the immunosuppressive phenotype of TAM. This work brings new information on the acquisition of immunosuppressive properties by tumor-infiltrating macrophages.