Interleukin 33 in tumor microenvironment is crucial for the accumulation and function of myeloid-derived suppressor cells
Interleukin 33 in tumor microenvironment is crucial for the accumulation and function of myeloid-derived suppressor cells
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肿瘤微环境中的白介素 33 对于骨髓源性抑制细胞的积累和功能至关重要。
DOI：
10.1080/2162402x.2015.1063772
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发表时间：
2016-01-01
期刊：
影响因子：
7.2
通讯作者：
Wang, Qingqing
中科院分区：
文献类型：
--
作者：
Xiao, Peng;Wan, Xiaopeng;Wang, Qingqing
肿瘤诱导的髓源性抑制细胞（MDSC）介导的免疫功能障碍是导致肿瘤免疫逃逸和癌症免疫治疗无效的重要机制。重要的是，肿瘤浸润性MDSC与外周中的MDSC相比具有更强的能力。然而，肿瘤微环境诱导MDSC的积累和功能的机制知之甚少。在这里，我们报告说，白细胞介素-33（IL-33）-一种细胞因子，可以在4 T1荷瘤小鼠和乳腺癌患者的肿瘤组织中大量释放，对于促进MDSC的扩增至关重要。肿瘤微环境中的IL-33通过诱导GM-CSF的自分泌，形成MDSC积聚的正放大环，从而减少MDSC的凋亡并维持MDSC的存活。这与IL-33驱动的MDSC中的TNF-α酶-1表达的诱导以及NF-κ B和MAPK信号传导的激活相结合，这增强了它们的免疫抑制能力，并且组蛋白修饰参与了MDSC中的IL-33信号传导。在ST 2（/）小鼠中，MDSC中IL-33信号传导的缺陷减弱了MDSC的免疫抑制和促肿瘤能力。我们的研究结果确定IL-33作为一种关键介质，有助于MDSC在肿瘤微环境中的异常扩增和增强免疫抑制功能，这可能是潜在的靶向逆转MDSC介导的肿瘤免疫逃避。
Tumor-induced, myeloid-derived suppressor cells (MDSCs)-mediated immune dysfunction is an important mechanism that leads to tumor immune escape and the inefficacy of cancer immunotherapy. Importantly, tumor-infiltrating MDSCs have much stronger ability compared to MDSCs in the periphery. However, the mechanisms that tumor microenvironment induces the accumulation and function of MDSCs are poorly understood. Here, we report that Interleukin-33 (IL-33) - a cytokine which can be abundantly released in tumor tissues both in 4T1-bearing mice and breast cancer patients, is crucial for facilitating the expansion of MDSCs. IL-33 in tumor microenvironment reduces the apoptosis and sustains the survival of MDSCs through induction of autocrine secretion of GM-CSF, which forms a positive amplifying loop for MDSC accumulation. This is in conjunction with IL-33-driven induction of arginase-1 expression and activation of NF-kappa B and MAPK signaling in MDSCs which augments their immunosuppressive ability, and histone modifications were involved in IL-33 signaling in MDSCs. In ST2 (/) mice, the defect of IL-33 signaling in MDSCs attenuates the immunosuppressive and pro-tumoral capacity of MDSCs. Our results identify IL-33 as a critical mediator that contributes to the abnormal expansion and enhanced immunosuppressive function of MDSCs within tumor microenvironment, which can be potentially targeted to reverse MDSC-mediated tumor immune evasion.