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

Autor:	Ehx G; Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montreal, QC H3C 3J7, Canada; Department of Medicine, Université de Montréal, Montreal, QC H3C 3J7, Canada., Larouche JD; Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montreal, QC H3C 3J7, Canada; Department of Medicine, Université de Montréal, Montreal, QC H3C 3J7, Canada., Durette C; Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montreal, QC H3C 3J7, Canada., Laverdure JP; Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montreal, QC H3C 3J7, Canada., Hesnard L; Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montreal, QC H3C 3J7, Canada; Department of Medicine, Université de Montréal, Montreal, QC H3C 3J7, Canada., Vincent K; Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montreal, QC H3C 3J7, Canada; Department of Medicine, Université de Montréal, Montreal, QC H3C 3J7, Canada., Hardy MP; Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montreal, QC H3C 3J7, Canada., Thériault C; Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montreal, QC H3C 3J7, Canada., Rulleau C; Centre de recherche de l'Hôpital Maisonneuve-Rosemont, Montréal, QC, Canada., Lanoix J; Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montreal, QC H3C 3J7, Canada., Bonneil E; Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montreal, QC H3C 3J7, Canada., Feghaly A; Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montreal, QC H3C 3J7, Canada., Apavaloaei A; Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montreal, QC H3C 3J7, Canada; Department of Medicine, Université de Montréal, Montreal, QC H3C 3J7, Canada., Noronha N; Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montreal, QC H3C 3J7, Canada; Department of Medicine, Université de Montréal, Montreal, QC H3C 3J7, Canada., Laumont CM; Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montreal, QC H3C 3J7, Canada; Department of Medicine, Université de Montréal, Montreal, QC H3C 3J7, Canada., Delisle JS; Department of Medicine, Université de Montréal, Montreal, QC H3C 3J7, Canada; Centre de recherche de l'Hôpital Maisonneuve-Rosemont, Montréal, QC, Canada; Division of Hematology, Maisonneuve-Rosemont Hospital, Montreal, QC H1T 2M4, Canada., Vago L; Unit of Immunogenetics, Leukemia Genomics and Immunobiology, IRCCS San Raffaele Scientific Institute, Milan, Italy., Hébert J; Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montreal, QC H3C 3J7, Canada; Department of Medicine, Université de Montréal, Montreal, QC H3C 3J7, Canada; Division of Hematology, Maisonneuve-Rosemont Hospital, Montreal, QC H1T 2M4, Canada., Sauvageau G; Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montreal, QC H3C 3J7, Canada; Department of Medicine, Université de Montréal, Montreal, QC H3C 3J7, Canada; Division of Hematology, Maisonneuve-Rosemont Hospital, Montreal, QC H1T 2M4, Canada., Lemieux S; Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montreal, QC H3C 3J7, Canada; Department of Biochemistry and Molecular Medicine, Université de Montréal, Montreal, QC H3C 3J7, Canada., Thibault P; Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montreal, QC H3C 3J7, Canada; Department of Chemistry, Université de Montréal, Montreal, QC H3C 3J7, Canada. Electronic address: pierre.thibault@umontreal.ca., Perreault C; Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montreal, QC H3C 3J7, Canada; Department of Medicine, Université de Montréal, Montreal, QC H3C 3J7, Canada. Electronic address: claude.perreault@umontreal.ca.
Jazyk:	angličtina
Zdroj:	Immunity [Immunity] 2021 Apr 13; Vol. 54 (4), pp. 737-752.e10. Date of Electronic Publication: 2021 Mar 18.
DOI:	10.1016/j.immuni.2021.03.001
Abstrakt:	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. Competing Interests: Declaration of interests G.E., M.-P.H., S.L., P.T., and C.P. are named inventors on a patent application filed by Université de Montréal and covering antigens described in this article. (Copyright © 2021 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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