Details

Autor(en) / Beteiligte

• 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

Titel

Mutual regulation of tumour vessel normalization and immunostimulatory reprogramming

Ist Teil von

• Nature (London), 2017-04, Vol.544 (7649), p.250-254

Ort / Verlag

England: Nature Publishing Group

Erscheinungsjahr

2017

Quelle

MEDLINE

Beschreibungen/Notizen

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