抗肿瘤免疫可调节血管正常化:Th1细胞功不可没
  • 阻断血管新生抑制肿瘤生长,但也促进转移,血管正常化,或可解决该矛盾;
  • 血管正常化的基因表达特征与免疫刺激通路相关,尤其是T淋巴细胞浸润或激活;
  • 免疫检查点抑制剂,激活CD4(+)T淋巴细胞,促进血管正常化;
  • 免疫缺陷小鼠异种移植患者来源的肿瘤,移植瘤的缺氧程度增加,过继性输入TH1细胞后,缺氧缓解;
  • TH1细胞在血管新生和免疫重建中发挥意外作用,可能成为免疫检查点抑制剂和抗血管新生疗效的标志物和决定因素。
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Nature [IF:42.778]

Mutual regulation of tumour vessel normalization and immunostimulatory reprogramming

肿瘤血管正常化和免疫刺激重建的共同调控

10.1038/nature21724

2017-04-03, Letter

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Blockade of angiogenesis can retard tumour growth, but may also paradoxically increase metastasis. This paradox may be resolved by vessel normalization, which involves increased pericyte coverage, improved tumour vessel perfusion, reduced vascular permeability, and consequently mitigated hypoxia. Although these processes alter tumour progression, their regulation is poorly understood. Here we show that type 1 T helper (TH1) cells play a crucial role in vessel normalization. Bioinformatic analyses revealed that gene expression features related to vessel normalization correlate with immunostimulatory pathways, especially T lymphocyte infiltration or activity. To delineate the causal relationship, we used various mouse models with vessel normalization or T lymphocyte deficiencies. Although disruption of vessel normalization reduced T lymphocyte infiltration as expected, reciprocal depletion or inactivation of CD4(+) T lymphocytes decreased vessel normalization, indicating a mutually regulatory loop. In addition, activation of CD4(+) T lymphocytes by immune checkpoint blockade increased vessel normalization. TH1 cells that secrete interferon-γ are a major population of cells associated with vessel normalization. Patient-derived xenograft tumours growing in immunodeficient mice exhibited enhanced hypoxia compared to the original tumours in immunocompetent humans, and hypoxia was reduced by adoptive TH1 transfer. Our findings elucidate an unexpected role of TH1 cells in vasculature and immune reprogramming. TH1 cells may be a marker and a determinant of both immune checkpoint blockade and anti-angiogenesis efficacy.

First Authors:
Lin Tian

Correspondence Authors:
Xiang H-F Zhang

All Authors:
Lin Tian,Amit Goldstein,Hai Wang,Hin Ching Lo,Ik Sun Kim,Thomas Welte,Kuanwei Sheng,Lacey E Dobrolecki,Xiaomei Zhang,Nagireddy Putluri,Thuy L Phung,Sendurai A Mani,Fabio Stossi,Arun Sreekumar,Michael A Mancini,William K Decker,Chenghang Zong,Michael T Lewis,Xiang H-F Zhang

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