Cancer Immunotherapy Using AIRE Conditioning of the Tumor Epitopeome

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Publication Details

Journal
Cancer Immunology Research
Published
2026-08-26
DOI
https://doi.org/10.1158/2326-6066.cir-25-1589
Primary Topic
Adrenal Hormones and Disorders
Type
article
Field-Weighted Citation Impact
0.00
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article

Cancer Immunotherapy Using AIRE Conditioning of the Tumor Epitopeome

Benjamin L. Kendall, Rosa M. Diaz Marcano, Elizabeth Appleton, Amanda L. Huff et al.
Cancer Immunology Research
Adrenal Hormones and Disorders
article

Cancer Immunotherapy Using AIRE Conditioning of the Tumor Epitopeome

Benjamin L. Kendall, Rosa M. Diaz Marcano, Elizabeth Appleton, Amanda L. Huff, José S. Pulido, Jill Thompson, Alan Melcher, Richard G. Vile, Sheeba Irshad, Thanich Sangsuwannukul, Matthew Schuelke, Alex Chen, Mason Webb, Madelyn Moore, Jason Tonne, Muriel Metko, Maria P. Chiriboga-Yerovi
article en

Abstract

T-cell immune tolerance is established in part through the activity of the Auto-immune Regulator (AIRE) transcription factor in the medullary thymic epithelial cells (mTEC) of the thymus. AIRE induces expression of peripheral tissue-specific self-antigens for presentation to naïve T cells to promote activation/deletion of autoreactive T cells. This traditional role of AIRE in mTECs is to prevent autoimmunity. Herein, we demonstrate that tumors mimic the role of AIRE in mTECs to evade immune rejection. We found that AIRE induced a profile of "selfness" at the RNA and protein levels which, when presented on major histocompatibility complexes, shielded the tumor from inherently self-tolerized T cells. Moreover, we describe an in vivo immunotherapy in which engineered changes in AIRE expression in tumor cells altered their profile of selfness, exposing both AIRE-modified and parental unmodified tumor cells to T-cell attack. Therefore, by re-setting the immunological selfness of cancer cells, this AIRE-mediated immunotherapy 1) converted a highly tolerized T-cell compartment into a tumor-reactive T-cell population; 2) conferred upon non-immunogenic tumors de novo sensitivity to immune checkpoint blockade; 3) removed the need to identify potentially immunogenic tumor-associated antigens as targets for generation of T-cell responses; and 4) lead to potent T cell-mediated rejection of aggressive, immunologically cold, non-immunogenic tumors. Patient RNA-sequencing data showed that expression of AIRE predicted response to immune therapies with a strong correlation between AIRE expression and markers of T-cell receptor signaling, suggesting our studies have therapeutic translational value.

Cancer Immunology Research
Mayo Clinic (US), Institute of Cancer Research (GB), Johns Hopkins University (US), King's College London (GB), Johns Hopkins Medicine (US), Institute of Cancer Research (CA), Mayo Clinic in Arizona (US), Mayo Clinic in Florida (US), CRUK Lung Cancer Centre of Excellence (GB), Johns Hopkins Hospital (US), Myriad Genetics (US), Wills Eye Hospital (US)
Openalex Percentile: Top 10%
Adrenal Hormones and Disorders
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