title: Rejection of leukemic cells requires antigen-specific T cells with high functional avidity.
abstract: In a context where injection of antigen (Ag)-specific T cells probably represents the future of leukemia immunotherapy, identification of optimal target Ags is crucial. We therefore sought to discover a reliable marker for selection of the most potent Ags. To this end, (1) we immunized mice against 8 individual Ags: 4 minor histocompatibility Ags (miHAs) and 4 leukemia-associated Ags (LAAs) that were overexpressed on leukemic relative to normal thymocytes; (2) we assessed their ability to reject EL4 leukemic cells; and (3) we correlated the properties of our Ags (and their cognate T cells) with their ability to induce protective antileukemic responses. Overall, individual miHAs instigated more potent antileukemic responses than LAAs. Three features had no influence on the ability of primed T cells to reject leukemic cells: (1) MHC-peptide affinity; (2) the stability of MHC-peptide complexes; and (3) epitope density at the surface of leukemic cells, as assessed using mass spectrometry. The cardinal feature of successful Ags is that they were recognized by high-avidity CD8 T cells that proliferated extensively in vivo. Our work suggests that in vitro evaluation of functional avidity represents the best criterion for selection of Ags, which should be prioritized in clinical trials of leukemia immunotherapy.
authors.affiliation: Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, Quebec, Canada; Department of Medicine, Université de Montréal, Montréal, Quebec, Canada.
authors.forename: Krystel
authors.initials: K
authors.lastname: Vincent
authors.affiliation: Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, Quebec, Canada; Department of Medicine, Université de Montréal, Montréal, Quebec, Canada.
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Hardy
authors.affiliation: Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, Quebec, Canada; Department of Medicine, Université de Montréal, Montréal, Quebec, Canada.
authors.forename: Assya
authors.initials: A
authors.lastname: Trofimov
authors.affiliation: Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, Quebec, Canada; Department of Medicine, Université de Montréal, Montréal, Quebec, Canada.
authors.forename: Céline M
authors.initials: CM
authors.lastname: Laumont
authors.affiliation: Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, Quebec, Canada; Department of Chemistry, Université de Montréal, Montréal, Quebec, Canada.
authors.forename: Dev
authors.initials: D
authors.lastname: Sriranganadane
authors.affiliation: Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, Quebec, Canada; Department of Medicine, Université de Montréal, Montréal, Quebec, Canada.
authors.forename: Sarah
authors.initials: S
authors.lastname: Hadj-Mimoune
authors.affiliation: Department of Microbiology, Infectiology and Immunology, Université de Montréal, Montréal, Quebec, Canada.
authors.forename: Insaf
authors.initials: I
authors.lastname: Salem Fourati
authors.affiliation: Department of Microbiology, Infectiology and Immunology, Université de Montréal, Montréal, Quebec, Canada.
authors.forename: Hugo
authors.initials: H
authors.lastname: Soudeyns
authors.affiliation: Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, Quebec, Canada; Department of Chemistry, Université de Montréal, Montréal, Quebec, Canada.
authors.forename: Pierre
authors.initials: P
authors.lastname: Thibault
authors.affiliation: Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, Quebec, Canada; Department of Medicine, Université de Montréal, Montréal, Quebec, Canada. Electronic address: claude.perreault@umontreal.ca.
authors.forename: Claude
authors.initials: C
authors.lastname: Perreault
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000637:transplantation; D049109:Cell Proliferation; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology; D005260:Female; D015870:Gene Expression; D007114:Immunization; D016219:Immunotherapy, Adoptive; D008285:Major Histocompatibility Complex / Q000235:genetics; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D015778:Minor Histocompatibility Antigens / Q000235:genetics / Q000276:immunology*; D010455:Peptides / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D060168:Thymocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology
chemical_list: D000951:Antigens, Neoplasm; D018984:Epitopes, T-Lymphocyte; D015778:Minor Histocompatibility Antigens; D010455:Peptides
keywords: CD8 T lymphocyte; Leukemia immunotherapy; Leukemia-associated antigen; Major histocompatibility complex; Minor histocompatibility antigen