Macrophage expression of hypoxia-inducible factor-1α suppresses T-cell function and promotes tumor progression

Andrew L. Doedens, Christian Stockmann, Mark P. Rubinstein, Debbie Liao, Na Zhang, David G. DeNardo, Lisa Coussens, Michael Karin, Ananda W. Goldrath, Randall S. Johnson

Research output: Contribution to journalArticle

271 Citations (Scopus)

Abstract

T cells can inhibit tumor growth, but their function in the tumor microenvironment is often suppressed. Many solid tumors exhibit abundant macrophage infiltration and low oxygen tension, yet how hypoxic conditions may affect innate immune cells and their role in tumor progression is poorly understood. Targeted deletion of the hypoxia-responsive transcription factor hypoxia-inducible factor-1α (HIF-1α) in macrophages in a progressive murine model of breast cancer resulted in reduced tumor growth, although vascular endothelial growth factor-A levels and vascularization were unchanged. Tumor-associated macrophages can suppress tumor-infiltrating T cells by several mechanisms, and we found that hypoxia powerfully augmented macrophage-mediated T-cell suppression in vitro in a manner dependent on macrophage expression of HIF-1α. Our findings link the innate immune hypoxic response to tumor progression through induction of T-cell suppression in the tumor microenvironment.

Original languageEnglish (US)
Pages (from-to)7465-7475
Number of pages11
JournalCancer Research
Volume70
Issue number19
DOIs
StatePublished - Oct 1 2010
Externally publishedYes

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Hypoxia-Inducible Factor 1
Macrophages
T-Lymphocytes
Neoplasms
Tumor Microenvironment
Growth
Innate Immunity
Vascular Endothelial Growth Factor A
Transcription Factors
Breast Neoplasms
Oxygen

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Doedens, A. L., Stockmann, C., Rubinstein, M. P., Liao, D., Zhang, N., DeNardo, D. G., ... Johnson, R. S. (2010). Macrophage expression of hypoxia-inducible factor-1α suppresses T-cell function and promotes tumor progression. Cancer Research, 70(19), 7465-7475. https://doi.org/10.1158/0008-5472.CAN-10-1439

Macrophage expression of hypoxia-inducible factor-1α suppresses T-cell function and promotes tumor progression. / Doedens, Andrew L.; Stockmann, Christian; Rubinstein, Mark P.; Liao, Debbie; Zhang, Na; DeNardo, David G.; Coussens, Lisa; Karin, Michael; Goldrath, Ananda W.; Johnson, Randall S.

In: Cancer Research, Vol. 70, No. 19, 01.10.2010, p. 7465-7475.

Research output: Contribution to journalArticle

Doedens, AL, Stockmann, C, Rubinstein, MP, Liao, D, Zhang, N, DeNardo, DG, Coussens, L, Karin, M, Goldrath, AW & Johnson, RS 2010, 'Macrophage expression of hypoxia-inducible factor-1α suppresses T-cell function and promotes tumor progression', Cancer Research, vol. 70, no. 19, pp. 7465-7475. https://doi.org/10.1158/0008-5472.CAN-10-1439
Doedens, Andrew L. ; Stockmann, Christian ; Rubinstein, Mark P. ; Liao, Debbie ; Zhang, Na ; DeNardo, David G. ; Coussens, Lisa ; Karin, Michael ; Goldrath, Ananda W. ; Johnson, Randall S. / Macrophage expression of hypoxia-inducible factor-1α suppresses T-cell function and promotes tumor progression. In: Cancer Research. 2010 ; Vol. 70, No. 19. pp. 7465-7475.
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