Atypical acute myeloid leukemia-specific transcripts generate shared and immunogenic MHC class-I-associated epitopes.

Acute myeloid leukemia (AML) has not benefited from innovative immunotherapies, mainly because of the lack of actionable immune targets. Using an original proteogenomic approach, we analyzed the major histocompatibility complex class I (MHC class I)-associated immunopeptidome of 19 primary AML samples and identified 58 tumor-specific antigens (TSAs). These TSAs bore no mutations and derived mainly (86%) from supposedly non-coding genomic regions. Two AML-specific aberrations were instrumental in the biogenesis of TSAs, intron retention, and epigenetic changes. Indeed, 48% of TSAs resulted from intron retention and translation, and their RNA expression correlated with mutations of epigenetic modifiers (e.g., DNMT3A). AML TSA-coding transcripts were highly shared among patients and were expressed in both blasts and leukemic stem cells. In AML patients, the predicted number of TSAs correlated with spontaneous expansion of cognate T cell receptor clonotypes, accumulation of activated cytotoxic T cells, immunoediting, and improved survival. These TSAs represent attractive targets for AML immunotherapy. [Display omitted] • The proteogenomic features of 58 acute myeloid leukemia (AML)-specific antigens • AML antigens result mainly from epigenetic changes and intron retention • AML antigens are coded by transcripts expressed in leukemic blasts and stem cells • AML antigens elicit CD8 T cell responses in vitro and in vivo The lack of suitable targets is the main obstacle to immunotherapy of acute myeloid leukemia (AML). Ehx et al. reveal the structure and genomic origin of 58 AML-specific antigens. Epigenetic changes and intron retention are instrumental in the biogenesis of these antigens that represent attractive targets for AML immunotherapy. [ABSTRACT FROM AUTHOR]