Hypoxia induces a state of immunogenic dormancy in non-small cell lung cancer by blocking protein translation of the MHC class I pathway associated with m5C hypermethylation of mRNA 3663

Adam W. Mailloux; Matthew G. Smith; Alexis Rebecca Ramos; Heena Panchal; Emily Witt; Jianling Bi; James Byrne

doi:10.1093/jimmun/vkaf283.1435

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Hypoxia induces a state of immunogenic dormancy in non-small cell lung cancer by blocking protein translation of the MHC class I pathway associated with m5C hypermethylation of mRNA 3663

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Hypoxia induces a state of immunogenic dormancy in non-small cell lung cancer by blocking protein translation of the MHC class I pathway associated with m5C hypermethylation of mRNA 3663

Adam W. Mailloux, Matthew G. Smith, Alexis Rebecca Ramos, Heena Panchal, Emily Witt, Jianling Bi and James Byrne

The Journal of immunology (1950), Vol.214(Supplement_1), vkaf2831435

11/01/2025

DOI: 10.1093/jimmun/vkaf283.1435

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Abstract

Abstract Description Deficiencies in the MHC class I presentation pathway (C1PP) drive immune evasion and resistance to immunotherapies in cancers, including non-small cell lung cancer (NSCLC). Understanding how the C1PP is disrupted is likely to uncover strategies to enhance tumor immunogenicity. Here, we show that hypoxia (low O2 in solid tumors) suppresses the protein translation (but not mRNA expression) of key IFN-γ-induced C1PP components in A549 NSCLC cells in a HIF-1α/2α independent manner. These components include the proteolytic subunits of the immunoproteasome, ER transporters, chaperones, and peptide-loading complexes. Immunopeptidomics revealed a significant reduction in the diversity and abundance of MHC class I-presented antigens under hypoxia, including dozens of neoantigens and tumor-associated antigens. Mechanistically, we identified hyper-m5C methylation in hypoxic mRNA as a likely driver of C1PP selective translational suppression using immunoblotting, ELISA, and direct m5C RNA mapping. Reversing this methylation with 5-azacitidine restored hypoxic C1PP protein translation. In vivo, hyperbaric oxygen therapy (HBOT) raised tumor O2, reduced tumor growth, enhanced T-cell effector function, and prolonged survival in s.c. murine NSCLC. This is the first evidence linking epitranscriptomic m5C modifications to C1PP regulation, and highlights HBOT as a promising strategy to restore tumor immunogenicity and improve therapeutic outcomes.

Animals - Rodent Cells - Stromal Cells Molecules - Antigens/Peptides/Epitopes MHC Processes - Antigen Presentation/Processing

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Title: Subtitle: Hypoxia induces a state of immunogenic dormancy in non-small cell lung cancer by blocking protein translation of the MHC class I pathway associated with m5C hypermethylation of mRNA 3663
Creators: Adam W. Mailloux
Matthew G. Smith - University of Iowa
Alexis Rebecca Ramos - University of Iowa
Heena Panchal
Emily Witt - University of Iowa
Jianling Bi - University of Iowa
James Byrne - University of Iowa Holden Comprehensive Cancer Center
Resource Type: Abstract
Publication Details: The Journal of immunology (1950), Vol.214(Supplement_1), vkaf2831435
DOI: 10.1093/jimmun/vkaf283.1435
ISSN: 0022-1767
eISSN: 1550-6606
Publisher: Oxford University Press
Grant note: NIH-NCI: CA214285-01A1 ACS: CAT-24-1414241-01-CAT
Supported by: NIH-NCI CA214285-01A1; ACS-IRG-18-164-43; ACS CAT-24-1414241-01-CAT
Alternative title: IMMUNOLOGY2025™ Abstracts
Language: English
Date published: 11/01/2025
Academic Unit: Microbiology and Immunology; Radiation Oncology
Record Identifier: 9985034935402771

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