Inflammation enhances myeloid-derived suppressor cell crosstalk by signaling through Toll-like receptor 4
Inflammation enhances myeloid-derived suppressor cell crosstalk by signaling through Toll-like receptor 4
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DOI：
10.1189/jlb.0708446
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发表时间：
2009-06-01
影响因子：
5.5
通讯作者：
Ostrand-Rosenberg, Suzanne
中科院分区：
文献类型：
--
作者：
Bunt, Stephanie K.;Clements, Virginia K.;Ostrand-Rosenberg, Suzanne
髓源性抑制细胞（MDSC）是抗肿瘤免疫的有效抑制剂，其通过阻断CD 4（+）和CD 8（+）T细胞的活化并通过其产生IL-10和下调巨噬细胞产生IL-12来促进2型免疫应答，从而促进肿瘤进展。MDSC在许多癌症患者中积累，是主动癌症免疫治疗的重要障碍。慢性炎症最近已显示出增强MDSC的积累并增加其对T细胞的抑制。这些发现使我们假设炎症通过诱导MDSC促进肿瘤进展，MDSC为肿瘤生长创造了有利的环境。由于慢性炎症也驱动2型免疫反应，这有利于肿瘤生长，我们询问炎症是否通过MDSC介导这种作用。我们发现，IL-1 β诱导的炎症增加了MDSC的IL-10产生，并诱导MDSC，与从炎症较少的肿瘤微环境中分离的MDSC相比，MDSC在下调巨噬细胞产生IL-12方面更有效，从而使肿瘤免疫向2型反应倾斜。炎症通过TLR 4途径的信号传导提高MDSC表型，并涉及CD 14的上调。虽然这种途径在其他髓样细胞中得到了很好的识别，但以前没有涉及MDSC功能。这些研究表明，MDSC是炎症促进2型免疫应答的中介，并且他们将MDSC中的TLR 4途径确定为下调免疫抑制和促进抗肿瘤免疫的潜在靶点。J. Leukoc. 85：996-1004; 2009.
Myeloid-derived suppressor cells (MDSC) are potent inhibitors of anti-tumor immunity that facilitate tumor progression by blocking the activation of CD4(+) and CD8(+) T cells and by promoting a type 2 immune response through their production of IL-10 and down-regulation of macrophage production of IL-12. MDSC accumulate in many cancer patients and are a significant impediment to active cancer immunotherapies. Chronic inflammation has been shown recently to enhance the accumulation of MDSC and to increase their suppression of T cells. These findings led us to hypothesize that inflammation contributes to tumor progression through the induction of MDSC, which create a favorable environment for tumor growth. As chronic inflammation also drives type 2 immune responses, which favor tumor growth, we asked if inflammation mediates this effect through MDSC. We find that IL-1 beta-induced inflammation increased IL-10 production by MDSC and induces MDSC, which are more effective at down-regulating macrophage production of IL-12 as compared with MDSC isolated from less-inflammatory tumor microenvironments, thereby skewing tumor immunity toward a type 2 response. Inflammation heightens MDSC phenotype by signaling through the TLR4 pathway and involves up-regulation of CD14. Although this pathway is well-recognized in other myeloid cells, it has not been implicated previously in MDSC function. These studies demonstrate that MDSC are an intermediary through which inflammation promotes type 2 immune responses, and they identify the TLR4 pathway in MDSC as a potential target for down-regulating immune suppression and promoting anti-tumor immunity. J. Leukoc. Biol. 85: 996-1004; 2009.