Mutual regulation of tumour vessel normalization and immunostimulatory reprogramming

Nature. 2017 Apr 13;544(7649):250-254. doi: 10.1038/nature21724. Epub 2017 Apr 3.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer
  • Animals
  • CD4-Positive T-Lymphocytes / cytology
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / transplantation
  • Capillary Permeability
  • Cell Hypoxia / physiology
  • Endothelial Cells / immunology
  • Endothelial Cells / physiology
  • Female
  • Humans
  • Interferon-gamma / immunology
  • Interferon-gamma / metabolism
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Neoplasms / blood supply*
  • Neoplasms / immunology*
  • Neoplasms / pathology
  • Neovascularization, Pathologic / immunology*
  • Neovascularization, Pathologic / pathology
  • Neovascularization, Physiologic / immunology*
  • Neovascularization, Physiologic / physiology*
  • Pericytes / cytology
  • Pericytes / physiology
  • Prognosis
  • Th1 Cells / cytology
  • Th1 Cells / immunology
  • Th1 Cells / metabolism
  • Th1 Cells / transplantation
  • Xenograft Model Antitumor Assays


  • Interferon-gamma