Autophagy degrades immunogenic endogenous retroelements induced by 5-azacytidine in acute myeloid leukemia

• Published in: Leukemia Vol. 38; no. 5; pp. 1019 - 1031
• Main Authors: Noronha, Nandita, Durette, Chantal, Cahuzac, Maxime, E Silva, Bianca, Courtois, Justine, Humeau, Juliette, Sauvat, Allan, Hardy, Marie-Pierre, Vincent, Krystel, Laverdure, Jean-Philippe, Lanoix, Joël, Baron, Frédéric, Thibault, Pierre, Perreault, Claude, Ehx, Gregory
• Format: Journal Article Web Resource
• Language: English
• Published: London Nature Publishing Group UK 01.05.2024; Nature Publishing Group; Springer Science and Business Media LLC
• Subjects: 14/19; 38/91; 631/208/69; 631/250/2152/1566/20; 631/250/580; 631/67/1990/283/1897; 82/58; 96/31; Acute myeloid leukemia; Antigens; Antigens, Neoplasm - genetics; Antigens, Neoplasm - immunology; Antimetabolites, Antineoplastic - pharmacology; Antimetabolites, Antineoplastic - therapeutic use; Autophagy; Autophagy - drug effects; Azacitidine - pharmacology; Azacytidine; Biochemistry, biophysics & molecular biology; Biochimie, biophysique & biologie moléculaire; Cancer Research; CD8 antigen; Cell Proliferation; Cell survival; Chemotherapy; Critical Care Medicine; Cytotoxicity; DNA Methylation - drug effects; Hematology; Humans; Immune response; Immunogenicity; Inflammation; Innate immunity; Intensive; Internal Medicine; Leukemia; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - immunology; Leukemia, Myeloid, Acute - pathology; Life sciences; Lymphocytes T; Major histocompatibility complex; Medicine; Medicine & Public Health; Oncology; Peptides; Sciences du vivant
• ISSN: 0887-6924; 1476-5551; 1476-5551
• DOI: 10.1038/s41375-024-02250-6

The hypomethylating agent 5-azacytidine (AZA) is the first-line treatment for AML patients unfit for intensive chemotherapy. The effect of AZA results in part from T-cell cytotoxic responses against MHC-I-associated peptides (MAPs) deriving from hypermethylated genomic regions such as cancer-testis antigens (CTAs), or endogenous retroelements (EREs). However, evidence supporting higher ERE MAPs presentation after AZA treatment is lacking. Therefore, using proteogenomics, we examined the impact of AZA on the repertoire of MAPs and their source transcripts. AZA-treated AML upregulated both CTA and ERE transcripts, but only CTA MAPs were presented at greater levels. Upregulated ERE transcripts triggered innate immune responses against double-stranded RNAs but were degraded by autophagy, and not processed into MAPs. Autophagy resulted from the formation of protein aggregates caused by AZA-dependent inhibition of DNMT2. Autophagy inhibition had an additive effect with AZA on AML cell proliferation and survival, increased ERE levels, increased pro-inflammatory responses, and generated immunogenic tumor-specific ERE-derived MAPs. Finally, autophagy was associated with a lower abundance of CD8 + T-cell markers in AML patients expressing high levels of EREs. This work demonstrates that AZA-induced EREs are degraded by autophagy and shows that inhibiting autophagy can improve the immune recognition of AML blasts in treated patients.