title: Ex vivo characterization of polyclonal memory CD8+ T-cell responses to PRAME-specific peptides in patients with acute lymphoblastic leukemia and acute and chronic myeloid leukemia.
abstract: Preferentially expressed antigen of melanoma (PRAME) is aberrantly expressed in hematologic malignancies and may be a useful target for immunotherapy in leukemia. To determine whether PRAME is naturally immunogenic, we studied CD8(+) T-cell responses to 4 HLA-A*0201-restricted PRAME-derived epitopes (PRA100, PRA142, PRA300, PRA425) in HLA-A*0201-positive patients with acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and healthy donors. CD8(+) T cells recognizing PRAME peptides could be detected ex vivo in 4 of 10 ALL, 6 of 10 AML, 3 of 10 CML patients, and 3 of 10 donors by HLA-A2 tetramer analysis and flow cytometry for intracellular interferon-gamma. The frequency of PRAME-specific CD8(+) T cells was greater in patients with AML, CML, and ALL than healthy controls. All peptides were immunogenic in patients, while responses were only detected to PRA300 in donors. High PRAME expression in patient peripheral blood mononuclear cells was associated with responses to greater than or equal to 2 PRAME epitopes compared with low PRAME expression levels (4/7 vs 0/23, P = .001), suggesting a PRAME-driven T-cell response. PRAME-specific T cells were readily expanded in short-term cultures in donors and patients. These results provide evidence for spontaneous T cell reactivity against multiple epitopes of PRAME in ALL, AML, and CML. The potential for developing PRAME as a target for immunotherapy in leukemia deserves further exploration.
authors.affiliation: Department of Hematology, Imperial College, Hammersmith Campus, London, United Kingdom. k.rezvani@imperial.ac.uk
authors.forename: Katayoun
authors.initials: K
authors.lastname: Rezvani
authors.forename: Agnes S M
authors.initials: AS
authors.lastname: Yong
authors.forename: Abdul
authors.initials: A
authors.lastname: Tawab
authors.forename: Behnam
authors.initials: B
authors.lastname: Jafarpour
authors.forename: Rhoda
authors.initials: R
authors.lastname: Eniafe
authors.forename: Stephan
authors.initials: S
authors.lastname: Mielke
authors.forename: Bipin N
authors.initials: BN
authors.lastname: Savani
authors.forename: Keyvan
authors.initials: K
authors.lastname: Keyvanfar
authors.forename: Yixin
authors.initials: Y
authors.lastname: Li
authors.forename: Roger
authors.initials: R
authors.lastname: Kurlander
authors.forename: A John
authors.initials: AJ
authors.lastname: Barrett
mesh_terms: D000951:Antigens, Neoplasm / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005434:Flow Cytometry; D015234:HLA-A Antigens / Q000276:immunology; D015789:HLA-A2 Antigen; D006801:Humans; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000096:biosynthesis; D007951:Leukemia, Myeloid / Q000276:immunology*; D010455:Peptides / Q000276:immunology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000951:Antigens, Neoplasm; D018984:Epitopes, T-Lymphocyte; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; C404944:PRAME protein, human; D010455:Peptides; D007371:Interferon-gamma