Cancer Exacerbates Ischemic Brain Injury Via Nrp1 (Neuropilin 1)-Mediated Accumulation of Regulatory T Cells Within the Tumor
Cancer Exacerbates Ischemic Brain Injury Via Nrp1 (Neuropilin 1)-Mediated Accumulation of Regulatory T Cells Within the Tumor
复制标题
癌症通过 Nrp1（神经毡蛋白 1）介导的肿瘤内调节性 T 细胞的积累加剧缺血性脑损伤
DOI：
10.1161/strokeaha.118.021948
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发表时间：
2018-11-01
期刊：
影响因子：
8.3
通讯作者：
Yu, Weifeng
中科院分区：
文献类型：
--
作者：
Wang, Long;Zhou, Yuxi;Yu, Weifeng
背景和目的调节性T细胞（Treg）的连续转移可预防卒中;然而，由于Treg的免疫抑制功能，基于Treg的治疗引起了对伴有癌症的卒中患者的关注。本研究的目的是探讨Tregs在脑缺血性脑损伤伴发癌症中的作用。方法为了建立癌症表型，在远端大脑中动脉闭塞手术前2至3周，将MC 38结肠癌或B16黑色素瘤细胞（5x 10（5）/小鼠）皮下注射到C57 BL/6 J小鼠体内。通过2，3，5-三苯基氯化四氮唑染色、免疫荧光染色、实时聚合酶链反应和流式细胞术测量脑体积、神经炎症和TcB浸润。机械，NRP 1（neuropilin-1）单克隆抗体用于在被转移到重组激活基因1（Rag 1-/-）中风小鼠中之前离体阻断Nrp 1对T细胞的作用，所述小鼠缺乏T和B细胞，或Nrp 1中和抗体全身注射到中风后携带癌症的野生型小鼠中。患有中风的荷瘤小鼠表现出增强的神经炎症和脑中更少的TdR，但在大脑中动脉远端闭塞后，更多的TdR明显浸润到肿瘤中。TdR的消耗增加了中风小鼠的梗死体积，但没有进一步加重患癌中风小鼠的脑损伤。Nrp 1阻断离体或Nrp 1全身中和减弱缺血性脑损伤和逆转肿瘤内积累的TGFAP中风后在荷癌mice.Conclusions Nrp 1信号通路介导的TGFAP肿瘤内积累可能在加重荷癌小鼠缺血性脑损伤中发挥关键作用，并可能代表一个有前途的免疫调节靶点的联合条件下的癌症和中风。
Background and Purpose Adoptive transfer of regulatory T cells (Tregs) protect against stroke; however, Treg-based therapy raises concerns in stroke patients with cancer because of the immunosuppressive function of Tregs. The purpose of this study was to investigate the role of Tregs in cerebral ischemic brain injury with concomitant cancer.Methods To establish a cancer phenotype, MC38 colon cancer or B16 melanoma cells (5x10(5)/mice) were injected subcutaneously into C57BL/6J mice 2 to 3 weeks before distal middle cerebral artery occlusion surgery. Infarct volume, neuroinflammation, and Tregs infiltration were measured by 2,3,5-triphenyltetrazolium chloride staining, immunofluorescence staining, real-time polymerase chain reaction, and flow cytometry. Mechanistically, Nrp1 (neuropilin-1) monoclonal antibody was used to block the Nrp1 effect on Tregs ex vivo before being transferred into recombination activating gene 1 (Rag1-/-) stroke mice, which are devoid of T and B cells, or a Nrp1 neutralization antibody was injected systemically into cancer-bearing wild-type mice after stroke.Results Cancer-bearing mice with stroke exhibited augmented neuroinflammation and fewer Tregs in the brain, but more infiltration of Tregs to the tumor was apparent after distal middle cerebral artery occlusion. Depletion of Tregs increased infarct volume in stroke mice but did not further exacerbate brain injury in cancer-bearing stroke mice. Nrp1 blocking ex vivo or Nrp1 systemic neutralization attenuated ischemic brain injury and reversed accumulation of Tregs within tumor after stroke in cancer-bearing mice.Conclusions Nrp1 signaling mediated accumulation of Tregs within tumor might play a critical role in exacerbating ischemic brain injury in cancer-bearing mice and may represent a promising immune modulatory target for the combined condition of cancer and stroke.