Hypoxia Induces Escape from Innate Immunity in Cancer Cells via Increased Expression of ADAM10: Role of Nitric Oxide
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Abstract
One key to malignant progression is the acquired ability of tumor cells to escape immune-mediated lysis. Whereas tumor hypoxia is known to play a causal role in cancer metastasis and resistance to therapy, the link between hypoxia and immune escape in cancer remains poorly understood. Here, we show that hypoxia induces tumor cell resistance to lysis mediated by immune effectors and that this resistance to lysis occurs via a hypoxia-inducible factor-1 (HIF-1)–dependent pathway linked to increased expression of the metalloproteinase ADAM10. This enzyme is required for the hypoxia-induced shedding of MHC class I chain–related molecule A (MICA), a ligand that triggers the cytolytic action of immune effectors, from the surface of tumor cells. Indeed, our findings show a mechanistic link between hypoxia-induced accumulation of the α-subunit of HIF-1 (HIF-1α), increased expression of ADAM10, and decreased surface MICA levels leading to tumor cell resistance to lysis mediated by innate immune effectors. Nitric oxide mimetic agents interfered with the hypoxia-induced accumulation of HIF-1α and with the hypoxia-induced upregulation of ADAM10 expression required for decreased surface MICA expression and resistance to lysis. Furthermore, treatment of tumor-bearing mice with nitroglycerin, a nitric oxide mimetic, attenuated tumor growth by a mechanism that relied upon innate immune effector cells. Together, these findings reveal a novel mechanism by which the hypoxic tumor microenvironment contributes to immune escape in cancer, lending support to potential immunotherapeutic strategies involving the use of nitric oxide mimetics. Cancer Res; 71(24); 7433–41. ©2011 AACR.
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Normoxic and hypoxic stabilization of HIF signaling in tumor cells promotes resistance to cytotoxic T lymphocyte-mediated lysis.
“Normoxic and hypoxic stabilization of HIF signaling in tumor cells promotes resistance to cytotoxic T lymphocyte–mediated lysis”
From Hypoxic control of metastasis (2016) · cites this paper as [53]
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- Authors
- Barsoum, I. B., Hamilton, T. K., Li, X., Cotechini, T., Miles, E. A., Siemens, D. R., & Graham, C. H.
- Affiliations
- Queen's University (CA)
- Venue
- Cancer Research
- Published
- 2011-12-15
- Volume
- 71
- Issue
- 24
- Pages
- 7433-7441
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W1969090863
- Cited by
- 188
- References
- 29
- Citations by year
- 2026: 9 · 2025: 13 · 2024: 6 · 2023: 19 · 2022: 22 · 2021: 16 · 2020: 16 · 2019: 14 · 2018: 13 · 2017: 7 · 2016: 11 · 2015: 14 · 2014: 9 · 2013: 10 · 2012: 9
- FWCI
- 3.05
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Canadian Institutes of Health Research
- 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 Cell Function and Interaction
- Keywords
- tumor hypoxia, immune evasion, ADAM10, nitric oxide, HIF-1α, nitroglycerin, tumor microenvironment, immunotherapy
- MeSH terms
- ADAM10 Protein, Animals, Flow Cytometry, Nitroglycerin, Humans, Immunity, Innate, Membrane Proteins, Mice, Nude, Neoplasms, Neoplasms, Experimental, Nitric Oxide, Transplantation, Heterologous, Vasodilator Agents, Blotting, Western, Histocompatibility Antigens Class I, Cell Hypoxia, RNA Interference, Cell Line, Tumor, Tumor Burden, Mice, ADAM Proteins, Hypoxia-Inducible Factor 1, alpha Subunit, Amyloid Precursor Protein Secretases, Tumor Microenvironment
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