Mutual regulation of tumour vessel normalization and immunostimulatory reprogramming
Open accessAbstract
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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Vascular normalization can increase immune cell infiltration into tumors.
“We previously demonstrated that vascular normalization could increase immune cells’ infiltration into tumors, and multiple studies have confirmed these findings in several tumor models (15,17-19).”
Better tumor blood vessels support adaptive antitumor immunity by helping tumor-infiltrating lymphocytes traffic and relocate, which improves results of immunotherapies such as immune checkpoint blockade.
“An improved vascular network favors adaptive antitumor immunity by promoting trafficking and re-localization of tumor-infiltrating lymphocytes (TILs), leading to improved outcomes of various immunotherapies, including immune checkpoint blockade (ICB) (15-20).”
IFNγ-secreting T cells are associated with vessel normalization, and IFNγ increases endothelial adhesion molecule expression.
“There is an association of IFNγ-secreting T cells and vessel normalization (18), and IFNγ promotes the enhanced expression of adhesion molecules in endothelial cells (65).”
Poor perfusion, tumor hypoxia, and T-cell exclusion are regarded as major resistance mechanisms.
“Lack of perfusion, tumoral hypoxia, and T-cell exclusion are considered significant resistance mechanisms (15,17-19).”
ICB of CTLA-4 and PD-1 can normalize blood vessels in multiple models of transplanted breast and other tumours.
“ICB of cytotoxic T lymphocyte protein 4 (CTLA-4) and PD-1 can normalize blood vessels in multiple models of transplanted breast and other tumours105.”
From Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges (2018) · cites this paper as [105]
ICB can have vessel-normalizing effects in preclinical models of breast tumours, although the kinetics of vascular normalization are unknown.
“ICB can have vessel-normalizing effects in preclinical models of breast tumours105, although the kinetics of vascular normalization are unknown.”
From Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges (2018) · cites this paper as [105]
The vascular normalization effect of CTLA-4 and PD-1 blockade was attributed to increased CD4+ TH1 cell accumulation and anticancer activity.
“The vascular normalization effect observed in this study was attributed to increased CD4+ type 1 T helper (TH1) cell accumulation and anticancer activity105.”
From Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges (2018) · cites this paper as [105]
The contrast between ICB-induced oedema in brain tumours and ICB-induced vascular normalization in breast cancer models suggests that vascular effects depend on tumour location and/or type.
“This observation contrasts with the vascular normalization induced by ICB in breast cancer models105 and suggests that the vascular effects are dependent on the tumour location and/or type — a possibility that needs to be further investigated.”
From Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges (2018) · cites this paper as [105]
The generalizability of reciprocal regulation of tumour vessel normalization and immunostimulatory reprogramming is supported by analyses of large transcriptomic databases in human tumours, but experimental studies were limited to breast cancer models.
“although the generalizability of the reciprocal regulation of tumour vessel normalization and immunostimulatory reprogramming is supported by analyses of large transcriptomic databases in human tumours, the experimental studies were limited to breast cancer models105.”
From Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges (2018) · cites this paper as [105]
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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
- Venue
- Nature
- Published
- 2017-04
- Volume
- 544
- Issue
- 7649
- Pages
- 250-254
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- 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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