Hypoxia and hypoxia-inducible factor (HIF) downregulate antigen-presenting MHC class I molecules limiting tumor cell recognition by T cells
Open accessAbstract
Human cancers are known to downregulate Major Histocompatibility Complex (MHC) class I expression thereby escaping recognition and rejection by anti-tumor T cells. Here we report that oxygen tension in the tumor microenvironment (TME) serves as an extrinsic cue that regulates antigen presentation by MHC class I molecules. In support of this view, hypoxia is shown to negatively regulate MHC expression in a HIF-dependent manner as evidenced by (i) lower MHC expression in the hypoxic TME in vivo and in hypoxic 3-dimensional (3D) but not 2-dimensional (2D) tumor cell cultures in vitro; (ii) decreased MHC in human renal cell carcinomas with constitutive expression of HIF due to genetic loss of von Hippel-Lindau (VHL) function as compared with isogenically paired cells with restored VHL function, and iii) increased MHC in tumor cells with siRNA-mediated knockdown of HIF. In addition, hypoxia downregulated antigen presenting proteins like TAP 1/2 and LMP7 that are known to have a dominant role in surface display of peptide-MHC complexes. Corroborating oxygen-dependent regulation of MHC antigen presentation, hyperoxia (60% oxygen) transcriptionally upregulated MHC expression and increased levels of TAP2, LMP2 and 7. In conclusion, this study reveals a novel mechanism by which intra-tumoral hypoxia and HIF can potentiate immune escape. It also suggests the use of hyperoxia to improve tumor cell-based cancer vaccines and for mining novel immune epitopes. Furthermore, this study highlights the advantage of 3D cell cultures in reproducing hypoxia-dependent changes observed in the TME.
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The parallel increase in NK cells enables killing of cancer cells that have downregulated the expression of class I MHC proteins to evade killing by T cells.
“Finally, the parallel increase in NK cells enables killing of cancer cells that have downregulated the expression of class I MHC proteins to evade killing by T cells (91, 92).”
From HIF inhibitor 32-134D eradicates murine hepatocellular carcinoma in combination with anti-PD1 therapy (2022) · cites this paper as [91]
The Introduction and Results report that reduced tumor MHC class I expression limits recognition and killing by cytotoxic T cells. The paper does not report a parallel increase in NK cells or show that NK cells kill those MHC-downregulated cancer cells; the only natural-killer-cell mention found is in a reference title. No page numbers were available in our copy. (LLM, conf=0.88)
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- Authors
- Sethumadhavan, S., Silva, M., Philbrook, P., Nguyen, T., Hatfield, S. M., Ohta, A., & Sitkovsky, M. V.
- Affiliations
- Northeastern University (US)
- Corresponding author
- Sitkovsky, Michail V.
- ORCID
- Venue
- PLOS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2017-11-20
- Volume
- 12
- Issue
- 11
- Pages
- e0187314
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC5695785
- OpenAlex
- W2769873734
- Cited by
- 119
- References
- 48
- Citations by year
- 2026: 6 · 2025: 20 · 2024: 12 · 2023: 19 · 2022: 11 · 2021: 15 · 2020: 19 · 2019: 13 · 2018: 4
- FWCI
- 4.46
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS ONE (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- National Institutes of Health (R01GM)
- National Cancer Institute (R01CA112561, R01CA111985)
- National Institute of General Medical Sciences (R01GM097320)
- National Center for Complementary and Integrative Health (R21AT002788)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Keywords
- tumor hypoxia, hypoxia-inducible factor, MHC class I downregulation, antigen presentation, tumor microenvironment, immune evasion, T cell recognition, VHL, LMP7, hyperoxia, renal cell carcinoma, cancer vaccines, immune epitopes
- MeSH terms
- ATP Binding Cassette Transporter, Subfamily B, Member 2, Antigen-Presenting Cells, Genes, MHC Class I, Humans, Kidney Neoplasms, Oxygen, T-Lymphocytes, Transcriptional Activation, Cell Hypoxia, Gene Expression Regulation, Neoplastic, Proteasome Endopeptidase Complex, Hypoxia-Inducible Factor 1, Von Hippel-Lindau Tumor Suppressor Protein, Tumor Microenvironment
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