Cited by 849Angiogenesis and VEGF in CancerCancer Immunotherapy and BiomarkersLymphatic System and Diseases

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Mutual regulation of tumour vessel normalization and immunostimulatory reprogramming

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Tian, Lin, Goldstein, Amit, Wang, Hai, Ching Lo, Hin, Sun Kim, Ik, Welte, Thomas, Sheng, Kuanwei, Dobrolecki, Lacey E., Zhang, Xiaomei, Putluri, Nagireddy, Phung, Thuy L., Mani, Sendurai A., Stossi, Fabio, Sreekumar, Arun, Mancini, Michael A., Decker, William K., Zong, Chenghang, Lewis, Michael T., Zhang, Xiang H.-F.·2017·Nature

DOI 10.1038/nature21724PMC PMC5788037

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Abstract

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 (T H 1) 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. T H 1 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 T H 1 transfer. Our findings elucidate an unexpected role of T H 1 cells in vasculature and immune reprogramming. T H 1 cells may be a marker and a determinant of both immune checkpoint blockade and anti-angiogenesis efficacy.

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Authors: Tian, L., Goldstein, A., Wang, H., Ching Lo, H., Sun Kim, I., Welte, T., Sheng, K., Dobrolecki, L. E., Zhang, X., Putluri, N., Phung, T. L., Mani, S. A., Stossi, F., Sreekumar, A., Mancini, M. A., Decker, W. K., Zong, C., Lewis, M. T., & Zhang, X. H.-F.
Affiliations: Baylor College of Medicine (US)
The University of Texas MD Anderson Cancer Center (US)
Corresponding author: Zhang, Xiaomei
Zhang, Xiang H.-F.
ORCID: Tian, Lin
Goldstein, Amit
Wang, Hai
Welte, Thomas
Sheng, Kuanwei
Dobrolecki, Lacey E.
Zhang, Xiaomei
Putluri, Nagireddy
Phung, Thuy L.
Mani, Sendurai A.
Stossi, Fabio
Sreekumar, Arun
Mancini, Michael A.
Decker, William K.
Zong, Chenghang
Lewis, Michael T.
Zhang, Xiang H.-F.
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2017-04
Volume: 544
Issue: 7649
Pages: 250-254
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature21724
PMC: PMC5788037
OpenAlex: W2601414401
Cited by: 841
References: 36
Citations by year: 2026: 88 · 2025: 98 · 2024: 98 · 2023: 100 · 2022: 92 · 2021: 129 · 2020: 97 · 2019: 63 · 2018: 51 · 2017: 25
FWCI: 26.46
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
RePEc: Research Papers in Economics (submittedVersion)
Funders: National Institutes of Health (1s10od016167-01)
National Cancer Institute (R00CA151293, R01CA220297, K99CA151293, R21CA185516, U01CA179674, R01CA183878, P30CA125123)
National Institute of Allergy and Infectious Diseases (P30AI036211, R01AI127387)
National Institute of Diabetes and Digestive and Kidney Diseases (P30DK056338)
National Center for Research Resources (S10RR024574)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Health Sciences › Medicine › Oncology › Lymphatic System and Diseases
Keywords: tumor immunosuppression, pericyte coverage, tumor hypoxia, CD4+ T cells, Th1 cells, interferon-gamma, immune checkpoint blockade, anti-angiogenic therapy, T cell infiltration, endothelial cells, tumor vasculature, patient-derived xenografts, cancer immunotherapy
MeSH terms: Animals, Capillary Permeability, Female, Humans, Interferon-gamma, Mice, Inbred BALB C, Mice, Inbred C57BL, Neoplasms, Neovascularization, Pathologic, Prognosis, CD4-Positive T-Lymphocytes, Cell Hypoxia, Lymphocytes, Tumor-Infiltrating, Th1 Cells, Neovascularization, Physiologic, Adoptive Transfer, Pericytes, Xenograft Model Antitumor Assays, Endothelial Cells, Mice

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