Journal Article

Mutual regulation of tumour vessel normalization and immunostimulatory reprogramming

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

2017

Overview

The cross-talk between immune cells and blood vessel endothelial cells promotes pericyte coverage and decreases hypoxia in mouse tumour models, and correlative evidence suggests that these processes influence cancer prognosis in humans. Normalizing tumour vasculature Tumours often develop with abnormal vasculature, characterized among other things by lower pericyte coverage of blood vessels, as well as leaky vessels that result in a hypoxic environment. Abnormal vessels limit immune infiltration and CD4 T cells can regulate angiogenesis. Using mouse models, the authors further dissect this crosstalk between immune cells and blood vessels in cancer, and describe a role for immune cells in normalizing the vasculature of tumours. The crosstalk between CD4 T cells and endothelial cells promotes pericyte coverage and decreases hypoxia, and correlative evidence suggests that these processes influence cancer prognosis in humans. The authors postulate that interventions that foster CD4 T-cell function, such as immune checkpoint blockade, also have a beneficial effect by normalizing the tumour vasculature. Blockade of angiogenesis can retard tumour growth, but may also paradoxically increase metastasis 1 , 2 . This paradox may be resolved by vessel normalization 3 , which involves increased pericyte coverage, improved tumour vessel perfusion, reduced vascular permeability, and consequently mitigated hypoxia 3 . 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 4 , 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/31 / 14/19 / 14/63 / 38/90 / 38/91 / 631/67/327 / 631/67/580 / 64/60 / Adoptive Transfer / Angiogenesis / Animals / Breast cancer / Capillary Permeability / CD4-Positive T-Lymphocytes - cytology / CD4-Positive T-Lymphocytes - immunology / CD4-Positive T-Lymphocytes - transplantation / Cell Hypoxia - physiology / Cytological research / Endothelial Cells - immunology / Endothelial Cells - physiology / Female / Gene expression / Genetic aspects / Humanities and Social Sciences / Humans / Hypoxia / Inactivation / Infiltration / Interferon-gamma - immunology / Interferon-gamma - metabolism / letter / Lymphocytes / Lymphocytes, Tumor-Infiltrating - immunology / Medical prognosis / Metastasis / Mice / Mice, Inbred BALB C / Mice, Inbred C57BL / multidisciplinary / Neoplasms - blood supply / Neoplasms - immunology / Neoplasms - pathology / Neovascularization / Neovascularization, Pathologic - immunology / Neovascularization, Pathologic - pathology / Neovascularization, Physiologic - immunology / Neovascularization, Physiologic - physiology / Pericytes - cytology / Pericytes - physiology / Permeability / Physiological aspects / Principal components analysis / Prognosis / Rodents / Science / Signatures / Smooth muscle / T cells / Th1 Cells - cytology / Th1 Cells - immunology / Th1 Cells - metabolism / Th1 Cells - transplantation / Tumor blood vessels / Tumors / Xenograft Model Antitumor Assays