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Cancer Cell. 2017 Nov 13;32(5):669-683.e5. doi: 10.1016/j.ccell.2017.10.003.

An HIF-1α/VEGF-A Axis in Cytotoxic T Cells Regulates Tumor Progression.

Author information

1
Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3EG, UK.
2
Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3EG, UK; Cancer Research UK, Cambridge Institute, Cambridge CB2 0RE, UK.
3
Cancer Research UK, Cambridge Institute, Cambridge CB2 0RE, UK.
4
Department of Cell and Molecular Biology, Karolinska Institute, 171 77 Stockholm, Sweden.
5
Molecular Biology Section, Division of Biological Sciences, University of California San Diego, La Jolla, CA 92161, USA.
6
Department of Clinical Sciences, Division of Oncology and Pathology, Lund University, 223 81 Lund, Sweden.
7
Karolinska Oncology, Karolinska Institute and University Hospital, 171 76 Stockholm, Sweden.
8
Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3EG, UK; Department of Cell and Molecular Biology, Karolinska Institute, 171 77 Stockholm, Sweden. Electronic address: rsj33@cam.ac.uk.

Abstract

Cytotoxic T cells infiltrating tumors are thought to utilize HIF transcription factors during adaptation to the hypoxic tumor microenvironment. Deletion analyses of the two key HIF isoforms found that HIF-1α, but not HIF-2α, was essential for the effector state in CD8+ T cells. Furthermore, loss of HIF-1α in CD8+ T cells reduced tumor infiltration and tumor cell killing, and altered tumor vascularization. Deletion of VEGF-A, an HIF target gene, in CD8+ T cells accelerated tumorigenesis while also altering vascularization. Analyses of human breast cancer showed inverse correlations between VEGF-A expression and CD8+ T cell infiltration, and a link between T cell infiltration and vascularization. These data demonstrate that the HIF-1α/VEGF-A axis is an essential aspect of tumor immunity.

KEYWORDS:

HIF transcription factors; VEGF; angiogenesis; cytotoxic T cells; hypoxia; immunotherapy

PMID:
29136509
PMCID:
PMC5691891
DOI:
10.1016/j.ccell.2017.10.003
[Indexed for MEDLINE]
Free PMC Article

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