From the Department of Anesthesiology (L.W., Y.Z., J.Y., X.W., D.W., L.Y., P.L., W.Y.), Renji Hospital, School of Medicine, Shanghai Jiaotong University, China.
Department of Anesthesia and Intensive Care, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China (L.W.).
Stroke. 2018 Nov;49(11):2733-2742. doi: 10.1161/STROKEAHA.118.021948.
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 (5×10/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.
背景与目的- 过继转移调节性 T 细胞（Tregs）可预防中风；然而，由于 Tregs 的免疫抑制功能，Treg 为基础的疗法在患有癌症的中风患者中引起了关注。本研究旨在探讨 Tregs 在伴发癌症的脑缺血性脑损伤中的作用。方法- 为了建立癌症表型，将 MC38 结肠癌细胞或 B16 黑色素瘤细胞（5×10/只小鼠）在远端大脑中动脉闭塞手术前 2 至 3 周皮下注射到 C57BL/6J 小鼠中。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梗死体积、神经炎症和 Tregs 浸润。在机制上，在将 Tregs 转移到缺乏 T 和 B 细胞的重组激活基因 1（Rag1-/-）中风小鼠之前，使用 Nrp1（神经纤毛蛋白-1）单克隆抗体在体外阻断 Nrp1 对 Tregs 的作用，或在癌症荷瘤野生型小鼠中风后系统注射 Nrp1 中和抗体。结果- 中风伴癌症的小鼠表现出增强的神经炎症和大脑中较少的 Tregs，但在大脑中动脉闭塞后，Tregs 向肿瘤的浸润更为明显。Tregs 的耗竭增加了中风小鼠的梗死体积，但在癌症伴中风的小鼠中并未进一步加重脑损伤。体外 Nrp1 阻断或 Nrp1 系统中和可减轻中风后荷瘤小鼠的缺血性脑损伤并逆转肿瘤内 Tregs 的积累。结论- Nrp1 信号介导的肿瘤内 Tregs 的积累可能在加重癌症荷瘤小鼠的缺血性脑损伤中起关键作用，并且可能代表癌症和中风合并症的有前途的免疫调节靶点。
