CD69 is a direct HIF-1α target gene in hypoxia as a mechanism enhancing expression on tumor-infiltrating T lymphocytes
Open accessAbstract
CD69 is an early activation marker on the surface of T lymphocytes undergoing activation by cognate antigen. We observed intense expression of CD69 on tumor-infiltrating T-lymphocytes that reside in the hypoxic tumor microenvironment and hypothesized that CD69 could be, at least partially, under the control of the transcriptional hypoxia response. In line with this, human and mouse CD3-stimulated lymphocytes cultured under hypoxia (1% O2) showed increased expression of CD69 at the protein and mRNA level. Consistent with these findings, mouse T lymphocytes that had recently undergone hypoxia in vivo, as denoted by pimonidazole staining, were more frequently CD69+ in the tumor and bone marrow hypoxic tissue compartments. We found evidence for HIF-1α involvement both when using T-lymphocytes from inducible HIF-1α−/− mice and when observing tumor-infiltrating T-lymphocytes in mice whose T cells are HIF-1α−/−. Direct pro-transcriptional activity of HIF-1α on a newly identified hypoxia response element (HRE) found in the human CD69 locus was demonstrated by ChIP experiments. These results uncover a connection between the HIF-1α oxygen-sensing pathway and CD69 immunobiology.
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Contradictory reports show a role of hypoxia in potentiating the activity of cytotoxic T cells, though these studies were mainly conducted in mouse models.
“Nevertheless, there are also contradictory reports showing the role of hypoxia in potentiating the activity of cytotoxic T cells, though these studies were mainly conducted in mouse models22–24.”
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Glycolysis‐Dependent Fatty Acid Metabolism Supports Human Tfh Cell Function
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- Authors
- Labiano, S., Meléndez-Rodríguez, F., Palazón, A., Teijeira, Á., Garasa, S., Etxeberria, I., Aznar, M. Á., Sánchez-Paulete, A. R., Azpilikueta, A., Bolaños, E., Molina, C., de la Fuente, H., Maiso, P., Sánchez-Madrid, F., de Landázuri, M. O., Aragonés, J., & Melero, I.
- Affiliations
- Navarre Institute of Health Research (ES)
- Research Unit, Santa Cristina Hospital, Research Institute Princesa (IP), Autonomous University of Madrid, Madrid, Spain
- University of Cambridge (GB)
- Immunology and Immunotherapy Department, Center for Applied Medical Research (CIMA) and Instituto de Investigación Sanitaria de Navarra (IdISNA), Pamplona, Spain
- Department of Vascular Biology and Inflammation, National Center for Cardiovascular Research (CNIC), Madrid, Spain
- Hospital Universitario Santa Cristina (ES)
- Corresponding author
- Melero, Ignacio
- ORCID
- Venue
- OncoImmunology
- Publisher
- Informa UK Limited
- Published
- 2017-01-19
- Volume
- 6
- Issue
- 4
- Pages
- e1283468
- ISSN
- 2162-4011 (ISSN-L)
- 2162-402X
- PMC
- PMC5414881
- OpenAlex
- W2574645689
- Cited by
- 35
- References
- 51
- Citations by year
- 2026: 4 · 2025: 2 · 2024: 2 · 2023: 7 · 2022: 6 · 2021: 7 · 2020: 3 · 2019: 1 · 2018: 2 · 2017: 1
- FWCI
- 0.64
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- OncoImmunology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Comunidad de Madrid (S2010/BMD-2542, INDISNET-S2011/BMD-2332, RD 12-0042-0056)
- Ministerio de Economía y Competitividad (SAF 2014-52361-R, SAF2014-55579R, SAF2013-46058-R, S2011/BMD-2332, SAF2011-22831)
- Banco Bilbao Vizcaya Argentaria
- Gobierno de Navarra
- Instituto de Salud Carlos III
- European Social Fund
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Keywords
- CD69, HIF-1α, hypoxia, tumor-infiltrating T cells, hypoxia response element, transcriptional regulation, oxygen sensing, T cell activation, tumor microenvironment, pimonidazole
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