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Targeting ST2 expressing activated regulatory T cells in Kras-mutant lung cancer.
OncoImmunology ( IF 6.5 ) Pub Date : 2019-11-02 , DOI: 10.1080/2162402x.2019.1682380
Byung-Seok Kim 1, 2 , Jelita Clinton 1 , Qing Wang 1 , Seon Hee Chang 1
Affiliation  

Oncogenic KRAS-mutant lung cancers remain treatment refractory. A better understanding of the immune response of KRAS-mutant lung cancers is required to facilitate the development of potential therapeutic strategies. Regulatory T cells (Tregs) are a subset of immune cells that promote tumor progression through suppressing anti-tumor immune response. Here, we used KrasG12D lung cancer mice to examine the characteristics of tumor-infiltrating Tregs. In tumor-bearing animals, Tregs are increased during tumor progression. Of note, a majority of Tregs that localized in lung tumors of Kras-mutant mice expressed ST2, a receptor for IL-33, which are different from Tregs in secondary lymphoid organs. To investigate the function of local Tregs influencing immune response in primary lung tumor development, we used anti-ST2 antibody to deplete Tregs in lung tumors of Kras-mutant mice. Treatment of Kras-mutant mice with anti-ST2 antibody resulted in depletion of activated Tregs in lung tumor while leaving Tregs in secondary lymphoid organs intact. Also, localized Tregs depletion led to a significant reduction in lung tumor burden. Immune response after Tregs depletion in tumors showed restoration of NK cell activity and enhanced Th1 activity, with increased CD8 cytotoxic T cell response. In addition, we found that the M2 macrophage signature in lung tumors was suppressed upon Tregs depletion, accompanied by upregulation of surface expression of MHC-II molecules and reduced expression of Arg1, Mmp12, Cxcl2, and Chi3l3. These data suggest that therapeutic strategies targeting activated Tregs in lung cancer have the potential to restrain tumor progression by enhancing anti-tumor immunity.

中文翻译:

在Kras突变型肺癌中靶向表达ST2的活化调节性T细胞。

致癌性KRAS突变型肺癌仍然难以治疗。需要更好地了解KRAS突变型肺癌的免疫应答,以促进潜在治疗策略的发展。调节性T细胞(Tregs)是免疫细胞的一个子集,可通过抑制抗肿瘤免疫反应来促进肿瘤进展。在这里,我们使用KrasG12D肺癌小鼠检查了肿瘤浸润Treg的特征。在荷瘤动物中,Tregs在肿瘤进展过程中增加。值得注意的是,大多数位于Kras突变小鼠的肺肿瘤中的Treg都表达ST2(IL-33的受体),与继发性淋巴器官的Treg不同。为了研究局部Tregs在原发性肺肿瘤发展中影响免疫应答的功能,我们使用了抗ST2抗体来耗尽Kras突变小鼠的肺肿瘤中的Treg。用抗ST2抗体治疗Kras突变小鼠导致肺肿瘤中活化的Treg耗竭,而继发性淋巴器官中的Treg则完好无损。同样,局部Tregs消耗导致肺肿瘤负担显着减少。肿瘤中Treg耗竭后的免疫反应显示NK细胞活性恢复和Th1活性增强,CD8细胞毒性T细胞反应增强。此外,我们发现肺肿瘤中的M2巨噬细胞签名在Treg耗竭后被抑制,伴随着MHC-II分子表面表达的上调和Arg1,Mmp12,Cxcl2和Chi3l3的表达降低。
更新日期:2019-11-02
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