To identify tumor-specific antigens (TSAs) in AML, Ehx et al. sequenced RNA from 19 patient tumors, subtracted sequences from medullary thymic cells and myelocytic progenitors, and evaluated each patient’s immunopeptidome. 58 high-probability TSAs (TSAhi) were found differentially expressed in AML cells compared to healthy tissues, and were derived not from mutations, but mostly from aberrantly-expressed non-coding regions. TSAhi expression correlated with patient survival, TCR clonotype enrichment, and CD8+ T cell activation, but also with signs of immunoediting (CD47, PD-L1, downregulation of antigen presentation) and epigenetic driver mutations.
Contributed by Alex Najibi
ABSTRACT: 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.
Author Info: (1) Institute for Research in Immunology and Cancer (IRIC), Universit de Montral, Montreal, QC H3C 3J7, Canada; Department of Medicine, Universit de Montral, Montreal, QC H3C 3J7,
Author Info: (1) Institute for Research in Immunology and Cancer (IRIC), Universit de Montral, Montreal, QC H3C 3J7, Canada; Department of Medicine, Universit de Montral, Montreal, QC H3C 3J7, Canada. (2) Institute for Research in Immunology and Cancer (IRIC), Universit de Montral, Montreal, QC H3C 3J7, Canada; Department of Medicine, Universit de Montral, Montreal, QC H3C 3J7, Canada. (3) Institute for Research in Immunology and Cancer (IRIC), Universit de Montral, Montreal, QC H3C 3J7, Canada. (4) Institute for Research in Immunology and Cancer (IRIC), Universit de Montral, Montreal, QC H3C 3J7, Canada. (5) Institute for Research in Immunology and Cancer (IRIC), Universit de Montral, Montreal, QC H3C 3J7, Canada; Department of Medicine, Universit de Montral, Montreal, QC H3C 3J7, Canada. (6) Institute for Research in Immunology and Cancer (IRIC), Universit de Montral, Montreal, QC H3C 3J7, Canada; Department of Medicine, Universit de Montral, Montreal, QC H3C 3J7, Canada. (7) Institute for Research in Immunology and Cancer (IRIC), Universit de Montral, Montreal, QC H3C 3J7, Canada. (8) Institute for Research in Immunology and Cancer (IRIC), Universit de Montral, Montreal, QC H3C 3J7, Canada. (9) Centre de recherche de l'Hpital Maisonneuve-Rosemont, Montral, QC, Canada. (10) Institute for Research in Immunology and Cancer (IRIC), Universit de Montral, Montreal, QC H3C 3J7, Canada. (11) Institute for Research in Immunology and Cancer (IRIC), Universit de Montral, Montreal, QC H3C 3J7, Canada. (12) Institute for Research in Immunology and Cancer (IRIC), Universit de Montral, Montreal, QC H3C 3J7, Canada. (13) Institute for Research in Immunology and Cancer (IRIC), Universit de Montral, Montreal, QC H3C 3J7, Canada; Department of Medicine, Universit de Montral, Montreal, QC H3C 3J7, Canada. (14) Institute for Research in Immunology and Cancer (IRIC), Universit de Montral, Montreal, QC H3C 3J7, Canada; Department of Medicine, Universit de Montral, Montreal, QC H3C 3J7, Canada. (15) Institute for Research in Immunology and Cancer (IRIC), Universit de Montral, Montreal, QC H3C 3J7, Canada; Department of Medicine, Universit de Montral, Montreal, QC H3C 3J7, Canada. (16) Department of Medicine, Universit de Montral, Montreal, QC H3C 3J7, Canada; Centre de recherche de l'Hpital Maisonneuve-Rosemont, Montral, QC, Canada; Division of Hematology, Maisonneuve-Rosemont Hospital, Montreal, QC H1T 2M4, Canada. (17) Unit of Immunogenetics, Leukemia Genomics and Immunobiology, IRCCS San Raffaele Scientific Institute, Milan, Italy. (18) Institute for Research in Immunology and Cancer (IRIC), Universit de Montral, Montreal, QC H3C 3J7, Canada; Department of Medicine, Universit de Montral, Montreal, QC H3C 3J7, Canada; Division of Hematology, Maisonneuve-Rosemont Hospital, Montreal, QC H1T 2M4, Canada. (19) Institute for Research in Immunology and Cancer (IRIC), Universit de Montral, Montreal, QC H3C 3J7, Canada; Department of Medicine, Universit de Montral, Montreal, QC H3C 3J7, Canada; Division of Hematology, Maisonneuve-Rosemont Hospital, Montreal, QC H1T 2M4, Canada. (20) Institute for Research in Immunology and Cancer (IRIC), Universit de Montral, Montreal, QC H3C 3J7, Canada; Department of Biochemistry and Molecular Medicine, Universit de Montral, Montreal, QC H3C 3J7, Canada. (21) Institute for Research in Immunology and Cancer (IRIC), Universit de Montral, Montreal, QC H3C 3J7, Canada; Department of Chemistry, Universit de Montral, Montreal, QC H3C 3J7, Canada. Electronic address: pierre.thibault@umontreal.ca. (22) Institute for Research in Immunology and Cancer (IRIC), Universit de Montral, Montreal, QC H3C 3J7, Canada; Department of Medicine, Universit de Montral, Montreal, QC H3C 3J7, Canada. Electronic address: claude.perreault@umontreal.ca.
