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

Research output: Contribution to journalArticle

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. 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.

Details

Authors
  • Asis Palazon
  • Petros A. Tyrakis
  • David Macias
  • Pedro Veliça
  • Helene Rundqvist
  • Susan Fitzpatrick
  • Nikola Vojnovic
  • Anthony T. Phan
  • Niklas Loman
  • Ingrid Hedenfalk
  • Thomas Hatschek
  • John Lövrot
  • Theodoros Foukakis
  • Ananda W. Goldrath
  • Jonas Bergh
  • Randall S. Johnson
Organisations
External organisations
  • University of Cambridge
  • Cancer Research UK
  • Karolinska Institutet
  • University of California, San Diego
  • Karolinska University Hospital
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cancer and Oncology

Keywords

  • angiogenesis, cytotoxic T cells, HIF transcription factors, hypoxia, immunotherapy, VEGF
Original languageEnglish
Pages (from-to)669-683.e5
JournalCancer Cell
Volume32
Issue number5
Publication statusPublished - 2017 Nov 13
Publication categoryResearch
Peer-reviewedYes