title: The role of antigen cross-presentation from leukemia blasts on immunity to the leukemia-associated antigen PR1.
abstract: Cross-presentation is an important mechanism by which exogenous tumor antigens are presented to elicit immunity. Because neutrophil elastase (NE) and proteinase-3 (P3) expression is increased in myeloid leukemia, we investigated whether NE and P3 are cross-presented by dendritic cells (DC) and B cells, and whether the NE and P3 source determines immune outcomes. We show that NE and P3 are elevated in leukemia patient serum and that levels correlate with remission status. We demonstrate cellular uptake of NE and P3 into lysosomes, ubiquitination, and proteasome processing for cross-presentation. Using anti-PR1/human leukocyte antigen-A2 monoclonal antibody, we provide direct evidence that B-cells cross-present soluble and leukemia-associated NE and P3, whereas DCs cross-present only leukemia-associated NE and P3. Cross-presentation occurred at early time points but was not associated with DC or B-cell activation, suggesting that NE and P3 cross-presentation may favor tolerance. Furthermore, we show aberrant subcellular localization of NE and P3 in leukemia blasts to compartments that share common elements of the classic major histocompatibility class I antigen-presenting pathway, which may facilitate cross-presentation. Our data demonstrate distinct mechanisms for cross-presentation of soluble and cell-associated NE and P3, which may be valuable in understanding immunity to PR1 in leukemia.
authors.affiliation: Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Gheath
authors.initials: G
authors.lastname: Alatrash
authors.forename: Yoko
authors.initials: Y
authors.lastname: Ono
authors.forename: Anna
authors.initials: A
authors.lastname: Sergeeva
authors.forename: Pariya
authors.initials: P
authors.lastname: Sukhumalchandra
authors.forename: Mao
authors.initials: M
authors.lastname: Zhang
authors.forename: Lisa S
authors.initials: LS
authors.lastname: St John
authors.forename: Tian-Hui
authors.initials: TH
authors.lastname: Yang
authors.forename: Kathryn
authors.initials: K
authors.lastname: Ruisaard
authors.forename: Paul M
authors.initials: PM
authors.lastname: Armistead
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Mittendorf
authors.forename: Hong
authors.initials: H
authors.lastname: He
authors.forename: Na
authors.initials: N
authors.lastname: Qiao
authors.forename: Tania
authors.initials: T
authors.lastname: Rodriguez-Cruz
authors.forename: Shoudan
authors.initials: S
authors.lastname: Liang
authors.forename: Karen
authors.initials: K
authors.lastname: Clise-Dwyer
authors.forename: Eric D
authors.initials: ED
authors.lastname: Wieder
authors.forename: Gregory
authors.initials: G
authors.lastname: Lizee
authors.forename: Sijie
authors.initials: S
authors.lastname: Lu
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Molldrem
mesh_terms: D000938:Antigen-Presenting Cells / Q000276:immunology; D000951:Antigens, Neoplasm / Q000276:immunology* / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology; D045744:Cell Line, Tumor; D045142:Cross-Priming / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D006801:Humans; D007938:Leukemia / Q000276:immunology*; D019272:Leukocyte Elastase / Q000276:immunology* / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D053146:Myeloblastin / Q000276:immunology* / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D021381:Protein Transport; D015398:Signal Transduction; D054875:Ubiquitination
chemical_list: D000951:Antigens, Neoplasm; D015395:Histocompatibility Antigens Class I; D019272:Leukocyte Elastase; D053146:Myeloblastin; D046988:Proteasome Endopeptidase Complex