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

Palazon, Asis; Tyrakis, Petros A.; Macias, David; Veliça, Pedro; Rundqvist, Helene; Fitzpatrick, Susan; Vojnovic, Nikola; Phan, Anthony T.; Loman, Niklas LU and Hedenfalk, Ingrid LU , et al. (2017) In Cancer Cell 32(5). p.5-683
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... (More)

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. Palazon et al. demonstrate the importance of the HIF-1α/VEGF-A axis in tumor immunity. HIF-1α, but not HIF-2α, drives CD8+ T cell glycolytic metabolism, migration, and effector function, while the HIF-1α transcriptional target VEGF-A contributes to tumor vascularization.

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Contribution to journal
publication status
published
subject
keywords
angiogenesis, cytotoxic T cells, HIF transcription factors, hypoxia, immunotherapy, VEGF
in
Cancer Cell
volume
32
issue
5
pages
5 - 683
publisher
Cell Press
external identifiers
  • scopus:85033695630
  • wos:000414965900015
ISSN
1535-6108
DOI
10.1016/j.ccell.2017.10.003
language
English
LU publication?
yes
id
874575c6-2836-43d1-8cdc-ddb17bda2a7b
date added to LUP
2017-11-28 07:17:09
date last changed
2018-04-29 04:43:56
@article{874575c6-2836-43d1-8cdc-ddb17bda2a7b,
  abstract     = {<p>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<sup>+</sup> T cells. Furthermore, loss of HIF-1α in CD8<sup>+</sup> T cells reduced tumor infiltration and tumor cell killing, and altered tumor vascularization. Deletion of VEGF-A, an HIF target gene, in CD8<sup>+</sup> T cells accelerated tumorigenesis while also altering vascularization. Analyses of human breast cancer showed inverse correlations between VEGF-A expression and CD8<sup>+</sup> 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. Palazon et al. demonstrate the importance of the HIF-1α/VEGF-A axis in tumor immunity. HIF-1α, but not HIF-2α, drives CD8<sup>+</sup> T cell glycolytic metabolism, migration, and effector function, while the HIF-1α transcriptional target VEGF-A contributes to tumor vascularization.</p>},
  author       = {Palazon, Asis and Tyrakis, Petros A. and Macias, David and Veliça, Pedro and Rundqvist, Helene and Fitzpatrick, Susan and Vojnovic, Nikola and Phan, Anthony T. and Loman, Niklas and Hedenfalk, Ingrid and Hatschek, Thomas and Lövrot, John and Foukakis, Theodoros and Goldrath, Ananda W. and Bergh, Jonas and Johnson, Randall S.},
  issn         = {1535-6108},
  keyword      = {angiogenesis,cytotoxic T cells,HIF transcription factors,hypoxia,immunotherapy,VEGF},
  language     = {eng},
  month        = {11},
  number       = {5},
  pages        = {5--683},
  publisher    = {Cell Press},
  series       = {Cancer Cell},
  title        = {An HIF-1α/VEGF-A Axis in Cytotoxic T Cells Regulates Tumor Progression},
  url          = {http://dx.doi.org/10.1016/j.ccell.2017.10.003},
  volume       = {32},
  year         = {2017},
}