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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Tumor-targeted TNFa stabilizes tumor vessels and enhances active immunotherapy
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Tumor-targeted TNFa stabilizes tumor vessels and enhances active immunotherapy

机译：靶向肿瘤的TNFa可稳定肿瘤血管并增强主动免疫治疗

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摘要

Solid tumors are intrinsically resistant to immune rejection. Abnormal tumor vasculature can act as a barrier for immune cell migration into tumors. We tested whether targeting IFNγ and/or TNFa into pancreatic neuroendocrine tumors can alleviate immune suppression. We found that intratumoral IFNγ causes rapid vessel loss, which does not support anti-tumor immunity. In contrast, low-dose TNFα enhances T-cell infiltration and overall survival, an effect that is exclusively mediated by CD8~+ effector cells. Intriguingly, lymphocyte influx does not correlate with increased vessel leakiness. Instead, low-dose TNFa stabilizes the vascular network and improves vessel perfusion. Inflammatory vessel remodeling is, at least in part, mediated by tumor-resident macrophages that are reprogrammed to secrete immune and angiogenic modulators. Moreover, inflammatory vessel remodeling with low-dose TNFa substantially improves anti-tumor vaccination or adoptive T-cell therapy. Thus, low-dose TNFa promotes both vessel remodeling and antitumor immune responses and acts as a potent adjuvant for active immunotherapy.
机译：实体瘤本质上对免疫排斥具有抵抗力。异常的肿瘤脉管系统可能会阻止免疫细胞迁移到肿瘤中。我们测试了将IFNγ和/或TNFa靶向胰腺神经内分泌肿瘤是否可以减轻免疫抑制。我们发现肿瘤内IFNγ导致血管快速丢失，这不支持抗肿瘤免疫。相比之下，低剂量TNFα增强T细胞浸润和总体存活，这种作用仅由CD8 +效应细胞介导。有趣的是，淋巴细胞流入与血管渗漏增加无关。相反，低剂量的TNFa可以稳定血管网络并改善血管灌注。炎性血管重塑至少部分地由驻留于肿瘤的巨噬细胞介导，所述巨噬细胞被重新编程以分泌免疫和血管生成调节剂。此外，用低剂量TNFa进行的炎症性血管重塑可大大改善抗肿瘤疫苗接种或过继性T细胞疗法。因此，低剂量的TNFa可以促进血管重塑和抗肿瘤免疫反应，并可以作为主动免疫治疗的有效佐剂。

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  • 作者

    Anna Johansson; Juliana Hamzah; Christine J. Payne; Ruth Ganss;

  • 作者单位

    Western Australian Institute for Medical Research, University of Western Australia, Centre for Medical Research, Laboratory for Cancer Medicine, Perth 6000,Australia;

    Bumham Institute for Medical Research, Department of Molecular, Cellular, and Developmental Biology, University of California Santa Barbara, CA 93106-9610;

    Western Australian Institute for Medical Research, University of Western Australia, Centre for Medical Research, Laboratory for Cancer Medicine, Perth 6000,Australia;

    Western Australian Institute for Medical Research, University of Western Australia, Centre for Medical Research, Laboratory for Cancer Medicine, Perth 6000,Australia;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    angiogenesis; vessel normalization; macrophage polarization;

    机译：血管生成;血管标准化巨噬细胞极化;

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