白细胞介素33对髓系来源抑制性细胞的功能调控及其在肿瘤免疫逃逸中的作用

It has now been consistently shown in many studies that a population of cells with suppressive activity (known as myeloid-derived suppressor cells, MDSCs) contributes to the negative regulation of immune responses during cancer and other diseases. MDSCs represent a heterogeneous population of myeloid cells in early differential stages that can be identified in mice by expression of CD11b and Gr-1. In addition to their depressive effect on host immune surveillance, MDSCs play critical roles in prompting of tumor invasion and metastasis. These cells are significantly expanded in tumor-bearing individuals while the mechanisms under their pathological expansion, recruitment and activation are poorly understood.Interleukin 33 (IL-33), a recently identified cytokine, has the ability to regulate the functions of various kinds of immune cells and involves multiple pathological processes, but its role in tumor immunity is still not clear. We found the comprehensive existence of IL-33 in human tumor tissues, and our preliminary data suggested that IL-33 had a great influence on the expansion and immune-suppressive ability of MDSCs. Based on these findings, this project aims to study the role and mechamisms of IL-33 in regulating the expansion and activation of myeloid-derived suppressor cells, as well as its influences on tumor immue escape, growth and metastasis, in addition to its celluar sources and regulatory factors in tumor microenvironment. We will use various animal tumor models including 4T1 murine metastatic breast cancer and human tumor models, ST-2 (IL-33 receptor) knock out mice and clinical tumor samples to perform these experiments. Our results might offer new opinions to clarify mechanisms of signal transduction during tumor immune escape, and more expectedly, to the novel strategies on cancer treatement and design of new potential therapeutic targets.

一群具有CD11b、Gr-1标志的髓系来源抑制性细胞(Myeloid-derived suppressor cells, MDSCs)与肿瘤进展的关系十分密切，在荷瘤宿主的器官及肿瘤局部大量聚集，但对其异常扩增、募集和活化的调控机制研究得尚不够深入。白细胞介素（IL-33）是近年发现的一种细胞因子，对多种免疫细胞均具有调节作用并参与各种病理过程，但与肿瘤免疫的关系还不清楚。我们前期发现，IL-33在肿瘤微环境中大量存在，初步的实验表明，IL-33对MDSC的存活和其免疫抑制功能有重要的调节作用。本研究项目利用4T1转移性乳腺癌等各种小鼠肿瘤模型和人肿瘤移植瘤模型、IL-33的受体（ST-2）敲除小鼠及临床肿瘤组织样本，研究IL-33对髓系来源抑制性细胞（MDSC）病理性扩增和功能活化的调控作用、分子机制及信号转导途径，阐明其在肿瘤免疫逃逸和肿瘤生长和转移中的作用，并揭示肿瘤微环境中IL-33的来源及其表达调控机制。研究结果可望在肿瘤免疫逃逸的机制方面提出新的学术观点，并可能为恶性肿瘤的免疫治疗和相关的药物研发提供新的思路以及潜在的治疗靶点。

髓系来源抑制性细胞（Myeloid derived suppressor cells, MDSC）是一群具有强大免疫抑制功能的细胞，在肿瘤局部可大量聚集，抑制免疫效应细胞尤其是T细胞的活性，并促进肿瘤细胞的侵袭和转移，对其异常扩增、募集和活化的调控机制研究得尚不够深入。本研究按计划顺利完成了项目计划书中的任务。利用4T1转移性乳腺癌等小鼠肿瘤模型、IL-33的受体（ST-2）敲除小鼠及临床肿瘤组织样本，分析了肿瘤微环境中IL-33的来源及其表达调控机制，揭示了IL-33对髓系来源抑制性细胞（MDSC）病理性扩增和功能活化的调控作用、分子机制及信号转导途径，IL-33能以GM-CSF自分泌的方式，在体内和体外促进MDSC的抗凋亡和增殖能力。NF-κB和ERK是IL-33调节MDSC 功能的关键性转录因子。MDSC在IL-33刺激后，ys-4 trimethylation (H3K4me3)水平显著上调，histone H3 Lys-14 acetylation (H3K14ac)水平也上升，说明IL-33调控MDSC功能的过程中涉及到表观修饰机制。本项目的研究还进一步拓展，利用肠炎诱导的小鼠肠癌模型和IL-27受体（WSX-1）的基因敲除小鼠阐明了肿瘤微环境中IL-27对髓系来源抑制性细胞（MDSC）的具体具有抑制作用，IL-27有可能作为潜在的抗肿瘤治疗的细胞因子。上述研究结果在深入阐明肿瘤免疫逃逸的机制方面提出了新的学术观点，并为靶向恶性肿瘤微环境的免疫治疗方法提供了新的思路和潜在的新靶点。通过本项目的研究，阐明了肿瘤微环境中的警报素IL-33促进髓系抑制性细胞聚集、存活和功能活化中所发挥的重要作用及其信号转导通路。同时，还揭示了IL-27对髓系抑制性细胞聚集的抑制作用。上述结果为阐明肿瘤的免疫逃逸机制提供了新的认识，并为免疫治疗的新策略提供了新的启示。研究成果在Oncoimmunology, J Mol Med等主流期刊发表3篇论文，培养了博士生4名和博士后1名，研究结果在冷泉港亚洲等国际学术会议上进行大会报告。