Hypoxia‐inducible factors in regulation of immune responses in tumour microenvironment

Kumar, Vinit; Gabrilovich, Dmitry I.

doi:10.1111/imm.12380

Cited by 329Cancer, Hypoxia, and MetabolismImmune cells in cancerCancer Immunotherapy and Biomarkers

Hypoxia‐inducible factors in regulation of immune responses in tumour microenvironment

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Kumar, Vinit, Gabrilovich, Dmitry I.·2014·Immunology

DOI 10.1111/imm.12380PMC PMC4253499

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Abstract

Summary: Hypoxia is one of the hallmarks of the tumour microenvironment. It is the result of insufficient blood supply to support proliferating tumour cells. In response to hypoxia, the cellular machinery uses mechanisms whereby the low level of oxygen is sensed and counterbalanced by changing the transcription of numerous genes. Hypoxia‐inducible factors ( HIF ) play a critical role in the regulation of cellular responses to hypoxia. In recent years ample evidence has indicated that HIF play a prominent role in tumour immune responses. Up‐regulation of HIF 1α promotes immune suppressive activity of myeloid‐derived suppressive cells ( MDSC ) and tumour‐associated macrophages ( TAM ) and rapid differentiation of MDSC to TAM . HIF 1 α does not affect MDSC differentiation to dendritic cells ( DC ) but instead causes DC activation. HIF inhibit effector functions of tumour‐infiltrating lymphocytes. HIF 1 α inhibits regulatory T ( T reg) cell development by switching the balance towards T helper type 17 cells. However, as a major part of T reg cell differentiation does not take place in the tumour site, a functionally more important role of HIF 1 α is in the promotion of T reg cell recruitment to the tumour site in response to chemokines. As a result, the presence of T reg cells inside tumours is increased. Hence, HIF play a largely negative role in the regulation of immune responses inside tumours. It appears that therapeutic strategies targeting HIF in the immune system could be beneficial for anti‐tumour immune responses.

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32-134D inhibited the expression of CD47, CD70, IL-6, and IL-10 mRNAs in immune or other stromal cell types, where HIFs play critical roles, rather than in tumor cells.
“which suggests that 32-134D inhibited the expression of these latter mRNAs in immune or other stromal cell types, where HIFs are known to play critical roles (56–61), rather than in tumor cells.”
From HIF inhibitor 32-134D eradicates murine hepatocellular carcinoma in combination with anti-PD1 therapy (2022) · cites this paper as [58]
Hypoxia and HIF promote an immunosuppressive microenvironment by recruiting regulatory T cells, MDSCs, and macrophages into the tumor microenvironment.
“Hypoxia and HIF promote an immunosuppressive microenvironment by recruiting regulatory T cells (Tregs), MDSCs, and macrophages into the tumor microenvironment”
From Hypoxic control of metastasis (2016) · cites this paper as [59]
Adenosine signals through A2A receptors on T cells to increase cyclic AMP, which inhibits T cell proliferation, expansion, and cytokine secretion.
“Adenosine signals through A2A receptors on T cells to increase cyclic adenosine 3′,5′-monophosphate, which inhibits T cell proliferation, expansion, and cytokine secretion”
From Hypoxic control of metastasis (2016) · cites this paper as [59]
Hypoxia inhibits the effector functions of tumor-infiltrating lymphocytes largely through accumulation of extracellular adenosine.
“hypoxia inhibits the effector functions of tumor-infiltrating lymphocytes largely through the accumulation of extracellular adenosine”
From Hypoxic control of metastasis (2016) · cites this paper as [59]

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Authors: Kumar, V., & Gabrilovich, D. I.
Affiliations: The Wistar Institute (US)
Corresponding author: Gabrilovich, Dmitry I.
ORCID: Gabrilovich, Dmitry I.
Venue: Immunology
Publisher: Wiley
Published: 2014-11-10
Volume: 143
Issue: 4
Pages: 512-519
ISSN: 0019-2805 (ISSN-L)
1365-2567
DOI: 10.1111/imm.12380
PMC: PMC4253499
OpenAlex: W2038974826
Cited by: 329
References: 82
Citations by year: 2026: 16 · 2025: 23 · 2024: 20 · 2023: 32 · 2022: 38 · 2021: 40 · 2020: 30 · 2019: 27 · 2018: 35 · 2017: 30 · 2016: 24 · 2015: 12 · 2014: 2
FWCI: 2.25
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations: Immunology (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: National Cancer Institute (CA 100062)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Keywords: hypoxia-inducible factor, HIF-1α, tumor microenvironment, tumor hypoxia, antitumor immunity, myeloid-derived suppressor cells, tumour-associated macrophages, dendritic cell activation, regulatory T cells, Th17 cells, tumor-infiltrating lymphocytes, chemokines, HIF-targeted therapy
MeSH terms: Animals, Hypoxia, Dendritic Cells, Humans, Macrophages, Neoplasms, Lymphocytes, Tumor-Infiltrating, Myeloid Cells, Hypoxia-Inducible Factor 1, Tumor Microenvironment

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Hypoxia‐inducible factors in regulation of immune responses in tumour microenvironment

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