Galectin-9 modulates immunity by promoting Th2/M2 differentiation and impacts survival in patients with metastatic melanoma.
Galectin-9 modulates immunity by promoting Th2/M2 differentiation and impacts survival in patients with metastatic melanoma.
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DOI：
10.1097/cmr.0000000000000281
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发表时间：
2016-10
影响因子：
2.2
通讯作者：
Markovic SN
中科院分区：
文献类型：
--
作者：
Enninga EA;Nevala WK;Holtan SG;Leontovich AA;Markovic SN
半乳糖凝集素-9是一种β-半乳糖苷结合蛋白，被定义为T辅助1 （Th1）免疫反应的负调节因子，有利于Th2偏向。转移性黑色素瘤患者的全身免疫主要是Th2偏倚。我们假设半乳糖凝集素-9可以调节晚期黑色素瘤患者对Th2极化的全身免疫。在转移性黑色素瘤患者的肿瘤和血浆中分别评估半乳糖凝集素-9的存在/浓度。通过体外暴露人外周血单个核细胞（PBMC），研究了半乳糖凝集素-9的免疫调节功能。半乳糖凝集素-9在57%的肿瘤中表达，与健康对照组相比，晚期黑色素瘤患者血浆中的半乳糖凝集素-9显著（3.6倍）增加（p<0.001）。高血浆半乳糖凝集素-9浓度与全身Th2极化有关，与低/无半乳糖凝集素-9表达相比，两年生存率降低。在体外，半乳糖凝集素-9减少健康pbmc的增殖，促进Th1细胞凋亡，并促进Th2偏向细胞表型和细胞因子分泌。通过趋化因子/细胞因子分泌和CD206表达来评估，在体外和转移性黑色素瘤患者中观察到，半凝集素-9也刺激单核细胞向M2巨噬细胞表型分化。转移性黑色素瘤患者血浆中半乳糖凝集素-9升高与Th2系统性偏倚和不太有利的临床结果相关。这种Th2偏倚似乎不仅是通过Tim3结合Th1凋亡的已知机制的一个特征，而且还通过髓样细胞向M2表型分化介导，可能有利于肿瘤进展。这些数据支持半乳糖凝集素-9作为转移性黑色素瘤患者的新治疗靶点。
Galectin-9, a β-galactoside binding protein, is defined as a negative regulator of T helper 1 (Th1) immune responses, favoring Th2 bias. Systemic immunity in patients with metastatic melanoma is predominately Th2 biased. We hypothesized galectin-9 could modulate systemic immunity toward Th2 polarization in patients with advanced melanoma. Presence/concentration of galectin-9 was assessed in tumors and plasma, respectively, in patients with metastatic melanoma. Immunomodulatory function of galectin-9 was determined by exposing human peripheral blood mononuclear cells (PBMC) to galectin-9 in vitro. Galectin-9 was expressed in 57% of tumors and was significantly (3.6-fold) increased in the plasma of patients with advanced melanoma compared to healthy controls (p<0.001). High plasma galectin-9 concentration was associated with systemic Th2 polarization and reduced two-year survival compared to low/no galectin-9 expression. In vitro, galectin-9 reduced proliferation of healthy PBMCs, promoted Th1 cell apoptosis, and encouraged Th2 biased cell phenotypes and cytokine secretion. Galectin-9 also stimulated monocyte differentiation towards an M2 macrophage phenotype, as assessed by chemokine/cytokine secretion and CD206 expression, observed both in vitro as well as in patients with metastatic melanoma. Elevated galectin-9 in patient plasma correlates with Th2 systemic bias and less favorable clinical outcomes in metastatic melanoma. This Th2 bias appears to be not only a feature of the known mechanisms of Th1 apoptosis via Tim3 binding, but also mediated via myeloid cell differentiation towards a M2 phenotype, potentially favoring tumor progression. These data support galectin-9 as a novel therapeutic target for patients with metastatic melanoma.