TREM-2 serves as a negative immune regulator through Syk pathway in an IL-10 dependent manner in lung cancer.
TREM-2 serves as a negative immune regulator through Syk pathway in an IL-10 dependent manner in lung cancer.
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TREM-2 在肺癌中通过 Syk 通路以 IL-10 依赖性方式充当负性免疫调节剂
DOI：
10.18632/oncotarget.8813
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发表时间：
2016-05-17
期刊：
影响因子：
--
通讯作者：
Zhou J
中科院分区：
文献类型：
--
作者：
Yao Y;Li H;Chen J;Xu W;Yang G;Bao Z;Xia D;Lu G;Hu S;Zhou J
在感染过程中，髓样细胞上表达的触发受体-2 （TREM-2）抑制树突状细胞（DCs）和巨噬细胞（MΦs）的吞噬，并通过dnax -激活蛋白12 （DAP12）信号通路减少促炎细胞因子的释放。然而，TREM-2信号在癌症中的作用从未被阐明。在本研究中，我们发现TREM-2在荷瘤宿主外周血单核细胞上表达上调。3LL荷瘤小鼠肺中检测到较多TREM-2+ dc。另一方面，肺部MΦs上TREM-2的表达水平与肺癌的病理分期呈正相关。然而，手术或化疗减轻肿瘤负荷导致TREM-2明显下降。体外，用含有3LL细胞上清的条件培养基（CM）诱导骨髓（BM）来源的dc和MΦs的TREM-2表达。CM和/或荷瘤小鼠的TREM-2+ dc表型改变（CD80LowCD86LowMHCIILow），功能受损，如白细胞介素(IL)-12分泌减少，IL-10产生增加，卵清蛋白(OVA)-内吞能力减弱；也对T细胞增殖产生了强有力的抑制作用，这种抑制作用可以通过阻断TREM-2部分逆转。脾酪氨酸激酶（Syk）抑制剂抑制TREM-2+DC细胞IL-10的产生。IL-10中和抗体和Syk抑制剂显著降低TREM-2+ dc对T细胞增殖的抑制潜能。此外，这种TREM-2+ dc的过继转移加速了肺癌小鼠的肿瘤生长，而不是损害其生存。综上所述，TREM-2可能以依赖IL-10的方式通过Syk通路作为负性免疫调节分子，部分预测肺癌患者的预后。
During infection, triggering receptor expressed on myeloid cells-2 (TREM-2) restrains dendritic cells (DCs) and macrophages (MΦs) phagocytosis, as well as reduces pro-inflammatory cytokines release through DNAX-activation protein 12 (DAP12) signaling. However, the role of TREM-2 signaling in cancer has never been elucidated. In the current study, we found that TREM-2 was up-regulated on peripheral blood monocytes in tumor-bearing host. More TREM-2+DCs were detected in the lung of 3LL tumor-bearing mice. On the other hand, the level of TREM-2 on pulmonary MΦs positively correlated with the pathological staging of lung cancer. However, surgical or chemotherapeutic reduction of tumor burden led to the obvious decline of TREM-2. In vitro, TREM-2 expression of bone marrow (BM)-derived DCs and MΦs was induced by conditional medium (CM) containing the supernatant of 3LL cells. TREM-2+DCs from CM and/or tumor-bearing mice held altered phenotypes (CD80LowCD86LowMHCIILow) and impaired functions, such as, reduced interleukin (IL)-12 secretion, increased IL-10 production, and weakened ovalbumin (OVA)-endocytic capacity; also developed potent inhibitory effect on T cell proliferation that could be partially reversed by TREM-2 blockage. Moreover, spleen tyrosine kinase (Syk) inhibitor restrained IL-10 production of TREM-2+DC. Remarkably, IL-10 neutralizing antibody and Syk inhibitor both lowered the suppressive potential of TREM-2+DCs in T cell proliferation. Also, adoptive transfer of this TREM-2+DCs accelerated the tumor growth rather than jeopardized survival in lung cancer-bearing mice. In conclusion, these results indicate that TREM-2 might act as a negative immuno-regulatory molecule through Syk pathway in an IL-10 dependent manner and partially predicts prognosis in lung cancer patients.
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