Mutual Regulation of Tumour Vessel Normalization and Immunostimulatory Reprogramming
By Lin Tian, A. Goldstein, Hai Wang, H. Lo, I. Kim, T. Welte, Kuanwei Sheng, L. Dobrolecki, Xiaomei Zhang, N. Putluri and 9 more. Nature, 2017
730 citations recorded by the source corpus.
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.
Subfields: Cancer Research, Immunology, Molecular Biology
View Paper: https://www.semanticscholar.org/paper/ec54bff460b662780ea59a275903042d519521d6
How researchers see this paper
The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.
- D. Zeng
- R. Zhou
- J. Bin
- Y. Liao
- Min Shi
- W. Liao
- Jingwen Zhang
- Meiyi Li
Citations in the corpus
- Regulatory mechanisms of PD-1/PD-L1 in cancers (2024, background): “When Th cells are activated using immune checkpoint blockade methods, the ability for vascular normalization is strengthened [383].”
- Tumor Microenvironment Characterization in Gastric Cancer Identifies Prognostic and Immunotherapeutically Relevant Gene Signatures (2019, background): “These data offer mechanistic insights into the responses to immune-checkpoint blockade, suggesting that response to PD-L1 and PD-1 blockade is not only related to enhanced cytolytic activity, antigen processing, and IFNg pathway components (13, 75), but is also associated with inhibition of fibrobla”