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首页 » 癌症研究 » PLoS Genet:肿瘤免疫治疗新招数——利用寄生虫抵抗卵巢肿瘤

PLoS Genet:肿瘤免疫治疗新招数——利用寄生虫抵抗卵巢肿瘤

来源:生物谷 2016-07-26 17:57

2016年7月26日讯 /生物谷BIOON/ --最近科学家发现寄生虫分泌的一些特定蛋白能够引起小鼠自身免疫系统攻击卵巢肿瘤。该研究由美国达特茅斯盖瑟医学院的研究人员发表在国际学术期刊Plos Genetics上。

利用机体自身免疫系统清除肿瘤细胞是对抗癌症的一种非常具有前景的方法,但是由于体内存在免疫耐受现象,免疫系统有时无法辨别需要被清除的细胞。

之前研究发现一种刚地弓形虫(T.gondii)疫苗株能够治愈小鼠的几种类型实体瘤,在这项新研究中,科学家们基于这些科学发现,进一步找到了究竟需要哪种寄生虫蛋白以及哪条免疫相关信号途径来打破肿瘤的免疫耐受。

在研究中研究人员在寄生虫体内有计划地删除了表达分泌效应蛋白的一些基因——在感染阶段寄生虫将这些分泌蛋白注入宿主细胞来影响免疫系统。随后他们将改造后的寄生虫注入恶性卵巢癌小鼠模型体内。研究结果显示T.gondii在感染宿主细胞前后分泌的特定棒状效应蛋白和致密颗粒效应蛋白能够引起宿主产生有效的抗肿瘤免疫应答,并且能够促进卵巢癌小鼠模型的存活。

研究人员认为利用具有感染性的有机体破坏肿瘤免疫耐受或是将来治疗癌症的一种最佳选择。目前利用单核细胞增生李斯特氏菌破坏胰腺肿瘤的免疫耐受已经进入临床试验阶段,而T.gondii可能会得到类似的应用。通过研究和理解这些T.gondii蛋白操纵的宿主细胞信号途径,科学家们可以发现潜在靶点,有望开发对抗高度恶性实体肿瘤的更有效方法。(生物谷Bioon.com)

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Barbara A. Fox,Kiah L. Sanders,Leah M. Rommereim,Rebekah B. Guevara,David J. Bzik

Nonreplicating type I uracil auxotrophic mutants of Toxoplasma gondii possess a potent ability to activate therapeutic immunity to established solid tumors by reversing immune suppression in the tumor microenvironment. Here we engineered targeted deletions of parasite secreted effector proteins using a genetically tractable Δku80 vaccine strain to show that the secretion of specific rhoptry (ROP) and dense granule (GRA) proteins by uracil auxotrophic mutants of T. gondii in conjunction with host cell invasion activates antitumor immunity through host responses involving CD8α+ dendritic cells, the IL-12/interferon-gamma (IFN-γ) TH1 axis, as well as CD4+ and CD8+ T cells. Deletion of parasitophorous vacuole membrane (PVM) associated proteins ROP5, ROP17, ROP18, ROP35 or ROP38, intravacuolar network associated dense granule proteins GRA2 or GRA12, and GRA24 which traffics past the PVM to the host cell nucleus severely abrogated the antitumor response. In contrast, deletion of other secreted effector molecules such as GRA15, GRA16, or ROP16 that manipulate host cell signaling and transcriptional pathways, or deletion of PVM associated ROP21 or GRA3 molecules did not affect the antitumor activity. Association of ROP18 with the PVM was found to be essential for the development of the antitumor responses. Surprisingly, the ROP18 kinase activity required for resistance to IFN-γ activated host innate immunity related GTPases and virulence was not essential for the antitumor response. These data show that PVM functions of parasite secreted effector molecules, including ROP18, manipulate host cell responses through ROP18 kinase virulence independent mechanisms to activate potent antitumor responses. Our results demonstrate that PVM associated rhoptry effector proteins secreted prior to host cell invasion and dense granule effector proteins localized to the intravacuolar network and host nucleus that are secreted after host cell invasion coordinately control the development of host immune responses that provide effective antitumor immunity against established ovarian cancer.

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