Hypoxia inhibits MHC I expression and antigen presentation to escape immune surveillance
Hypoxia is a common feature of solid tumors that has previously been linked to resistance to radiotherapy and chemotherapy, and more recently to immunotherapy. In particular, hypoxic tumors exclude T cells and inhibit their activity, suggesting that tumor cells acquire a mechanism to evade T cell re...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
EMBO Press
2025
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| _version_ | 1824458778628587520 |
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| author | Estephan, H Tailor, A Parker, R Kreamer, M Papandreou, I Campo, L Easton, A Moon, EJ Denko, N Ternette, N Hammond, E Giaccia, A |
| author_facet | Estephan, H Tailor, A Parker, R Kreamer, M Papandreou, I Campo, L Easton, A Moon, EJ Denko, N Ternette, N Hammond, E Giaccia, A |
| author_sort | Estephan, H |
| collection | OXFORD |
| description | Hypoxia is a common feature of solid tumors that has previously been linked to resistance to
radiotherapy and chemotherapy, and more recently to immunotherapy. In particular, hypoxic tumors
exclude T cells and inhibit their activity, suggesting that tumor cells acquire a mechanism to evade T
cell recognition and killing. Our analysis of hypoxic tumors indicates that hypoxia downregulates
MHC I expression and its bound peptides (the immunopeptidome). Hypoxia decreases MHC I
expression in an oxygen-dependent manner, mediated by the activation of autophagy through the
PERK arm of the unfolded protein response. Using an immunopeptidomics-based LC-MS approach,
we found a significant reduction in presented antigens under hypoxia. Inhibition of autophagy under
hypoxia enhanced antigen presentation. In experimental tumors, reducing mitochondrial metabolism
through a complex I inhibitor increases tumor oxygenation and both MHC I levels as well as the
immunopeptidome. These data provide the molecular mechanism governing tumor immune evasion in
hypoxic conditions, offering novel insights for therapeutic interventions targeting hypoxia-induced
alterations in antigen presentation. |
| first_indexed | 2024-12-09T03:20:03Z |
| format | Journal article |
| id | oxford-uuid:361f2c17-1c06-4fa4-816b-da9e11b7ccd0 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2025-02-19T04:31:18Z |
| publishDate | 2025 |
| publisher | EMBO Press |
| record_format | dspace |
| spelling | oxford-uuid:361f2c17-1c06-4fa4-816b-da9e11b7ccd02025-01-06T13:51:29ZHypoxia inhibits MHC I expression and antigen presentation to escape immune surveillanceJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:361f2c17-1c06-4fa4-816b-da9e11b7ccd0EnglishSymplectic ElementsEMBO Press2025Estephan, HTailor, AParker, RKreamer, MPapandreou, ICampo, LEaston, AMoon, EJDenko, NTernette, NHammond, EGiaccia, AHypoxia is a common feature of solid tumors that has previously been linked to resistance to radiotherapy and chemotherapy, and more recently to immunotherapy. In particular, hypoxic tumors exclude T cells and inhibit their activity, suggesting that tumor cells acquire a mechanism to evade T cell recognition and killing. Our analysis of hypoxic tumors indicates that hypoxia downregulates MHC I expression and its bound peptides (the immunopeptidome). Hypoxia decreases MHC I expression in an oxygen-dependent manner, mediated by the activation of autophagy through the PERK arm of the unfolded protein response. Using an immunopeptidomics-based LC-MS approach, we found a significant reduction in presented antigens under hypoxia. Inhibition of autophagy under hypoxia enhanced antigen presentation. In experimental tumors, reducing mitochondrial metabolism through a complex I inhibitor increases tumor oxygenation and both MHC I levels as well as the immunopeptidome. These data provide the molecular mechanism governing tumor immune evasion in hypoxic conditions, offering novel insights for therapeutic interventions targeting hypoxia-induced alterations in antigen presentation. |
| spellingShingle | Estephan, H Tailor, A Parker, R Kreamer, M Papandreou, I Campo, L Easton, A Moon, EJ Denko, N Ternette, N Hammond, E Giaccia, A Hypoxia inhibits MHC I expression and antigen presentation to escape immune surveillance |
| title | Hypoxia inhibits MHC I expression and antigen presentation to escape immune surveillance |
| title_full | Hypoxia inhibits MHC I expression and antigen presentation to escape immune surveillance |
| title_fullStr | Hypoxia inhibits MHC I expression and antigen presentation to escape immune surveillance |
| title_full_unstemmed | Hypoxia inhibits MHC I expression and antigen presentation to escape immune surveillance |
| title_short | Hypoxia inhibits MHC I expression and antigen presentation to escape immune surveillance |
| title_sort | hypoxia inhibits mhc i expression and antigen presentation to escape immune surveillance |
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