FcγRIIb调控MDSC极化在肿瘤进展中的作用

发布时间：2018-04-14 04:12

  本文选题：髓源性抑制细胞 + FcγRⅡb　； 参考：《扬州大学》2017年硕士论文

【摘要】：髓源性抑制细胞(myeloid-derived suppressor cell,MDSC)是一群具有很强免疫抑制功能的异质性细胞,与多种肿瘤的预后呈负相关,并降低肿瘤免疫治疗的效果。新近的研究指出:MDSC具有可塑性,可以在免疫刺激与免疫抑制表型,抗肿瘤与促肿瘤之间相互转换。如抗磷脂酰丝氨酸抗体能够诱导肿瘤组织中MDSC向免疫刺激表型极化;使用SHP-1抑制剂,肿瘤组织和脾脏中M-MDSC均能极化为免疫刺激型巨噬细胞,发挥抗肿瘤效应。因此,改变MDSC的极化状态,使其向免疫刺激表型极化是肿瘤免疫治疗的新思路。IgG的Fc段受体(FcγR)由活化性和抑制性两种功能相反的家族所组成。活化性FcγR种类很多,而抑制性FcγR在人和小鼠均只有一种,即FcγRⅡb,广泛表达于B细胞和髓系细胞表面。FcγRⅡb可调控多种免疫细胞的功能,如B细胞的FcγRⅡb可抑制由BCR引起的钙流、细胞增殖和抗体分泌;巨噬细胞表面的FcγRⅡb交联能够降低巨噬细胞吞噬能力和细胞因子分泌;FcγRⅡb能够抑制树突状细胞中活化型FcγR依赖的抗原内化和提呈功能。总之,FcγRⅡb能调控多种免疫细胞功能,但是FcγRⅡb能否调控肿瘤中的MDSC功能,到目前为止,国内外均未见相关报道。因此,在本研究中我们围绕FcγRⅡb对MDSC的调控作用进行了探讨。一、FcγRⅡb缺陷诱导MDSC向免疫刺激表型极化为了研究FcγRⅡb对MDSC功能有无影响,我们首先检测了肺癌细胞株3LL移植瘤小鼠体内MDSC表达FcγRⅡb的情况。结果发现,荷瘤小鼠骨髓、外周血、脾脏、肿瘤组织中CD11b+Gr-1+ MDSC均表达FcγRⅡb。既然MDSC表达FcγRⅡb,那么FcγRⅡb对MDSC的扩增和功能有无影响呢?我们利用WT(wild type,WT)和FcγRⅡb缺陷(FcγRⅡb-/-)小鼠制备了两种移植瘤模型(3LL和B16F10),在这两种模型中均发现:与WT相比,FcγRⅡb-/-小鼠脾脏中CD11b+Gr-1+MDSC比例明显增高。此外,我们比较了 WT和FcγRⅡb-/-移植瘤小鼠脾脏MDSC在细胞因子分泌、表面分子表达、酶活性及对T细胞功能影响上的差别。结果发现,与WT相比,FcγRⅡb-/-荷瘤小鼠脾脏MDSC中Ⅰ型精氨酸酶(arginase-1,ARG-1)活性、IL-10和CD206的表达明显下降,诱导型一氧化氮合成酶(inducible nitricoxide synthase,iNOS)活性、TNF-α、CCR7 和 IFN-γ受体的表达显著上调,CD11c、CD86和MHC Ⅱ类分子的表达没有明显变化。此外,与WT相比,FcγRⅡb-/-荷瘤小鼠脾脏MDSC对活化T细胞增殖的抑制作用以及对CD4+CD25+Foxp3++调节性T细胞的诱导作用明显下降。以上结果提示:FcγRⅡb缺陷诱导MDSC向免疫刺激表型极化。二、FcγRⅡb调控MDSC极化对肿瘤进展的影响为了研究FcγRⅡb-/-MDSC是否具有抗肿瘤效应,我们将WT MDSC和FcγRⅡb-/-MDSC分别过继回输给3LL荷瘤小鼠,检测荷瘤小鼠肿瘤的生长情况。结果发现:过继回输WT MDSC可促进肿瘤生长,而过继回输FcγRⅡb-/-MDSC则延缓肿瘤的生长,提示FcγRⅡb-/-使MDSC由促肿瘤向抗肿瘤效应转变。为了研究FcγRⅡb是否影响肿瘤的进展,我们分别给WT小鼠和FcγRⅡb-/-小鼠皮下成瘤(3LL或B16F10细胞),检测肿瘤的生长情况及小鼠的死亡率。结果在两种荷瘤模型中均发现:与WT小鼠相比,FcγRⅡb-/-小鼠体内的肿瘤生长缓慢且小鼠的死亡率明显下降,提示FcγRⅡb-/-抑制了小鼠肿瘤的进展。但这一现象是否与FcγRⅡb调控MDSC向免疫刺激表型极化有关,尚需通过抗体清除体内MDSC实验进一步证实。总之,本研究首次发现FcγRⅡb-/-调控MDSC向免疫刺激表型极化并使之向抗肿瘤效应转变。所得的结果不仅可揭示FcγRⅡb参与肿瘤发生发展的新机制,丰富对MDSC可塑性的认识,更可为研制以MDSC为靶标的新型防治策略提供理论基础。
[Abstract]:Myeloid derived suppressor cells (myeloid-derived suppressor cell, MDSC) is a group of heterogeneous cell has strong immunosuppressive function, and negatively related to the prognosis of many tumors, and reduce the effects of tumor immunotherapy. Recent studies suggest that MDSC has plasticity, can inhibit the phenotype in immune stimulation and immune, anti-tumor and the mutual conversion between cancer. Such as anti phosphatidylserine antibody can be induced by MDSC in tumor tissue to stimulate immune phenotype polarization; the use of SHP-1 inhibitors, M-MDSC tumor tissue and spleen were polarized into immune stimulation of macrophages, play the anti-tumor effect. Therefore, the change of polarization state of MDSC, which leads to immune phenotype polarization new ideas of tumor immunotherapy.IgG Fc receptor (Fc - R) consists of the activation and inhibition of the two functions of the opposite family. Activated Fc gamma R species is very much, and inhibition of Fc gamma R in human and mouse are only one, namely Fc gamma R II B, widely expressed in B cells and myeloid cell surface.Fc gamma R II B can regulate immune cell functions, such as B Fc gamma R II B cells could be inhibited by BCR induced calcium influx, cell proliferation and antibody secretion; the macrophage surface Fc gamma R II B crosslinking can reduce the phagocytosis of macrophage and cytokine secretion; Fc gamma R II B can activate Fc R gamma dependent antigen presenting function of internalization and inhibition of dendritic cells. In short, Fc gamma R II B can regulate immune cell function, but Fc gamma R II can b the regulation of tumor MDSC function, so far, both at home and abroad has not been reported. Therefore, the regulation role in this study we focus on Fc gamma R II B of MDSC was studied. A Fc gamma R II B defects induced by MDSC to immune phenotype polarization in order to study the Fc gamma R B on MDSC the function has no effect, we first examined 浜嗚偤鐧岀粏鑳炴牚3LL绉绘�嶇槫灏忛紶浣撳唴MDSC琛ㄨ揪Fc纬R鈪�b鐨勬儏鍐，

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