title: Broad cross-presentation of the hematopoietically derived PR1 antigen on solid tumors leads to susceptibility to PR1-targeted immunotherapy.
abstract: PR1 is a HLA-A2-restricted peptide that has been targeted successfully in myeloid leukemia with immunotherapy. PR1 is derived from the neutrophil granule proteases proteinase 3 (P3) and neutrophil elastase (NE), which are both found in the tumor microenvironment. We recently showed that P3 and NE are taken up and cross-presented by normal and leukemia-derived APCs, and that NE is taken up by breast cancer cells. We now extend our findings to show that P3 and NE are taken up and cross-presented by human solid tumors. We further show that PR1 cross-presentation renders human breast cancer and melanoma cells susceptible to killing by PR1-specific CTLs (PR1-CTL) and the anti-PR1/HLA-A2 Ab 8F4. We also show PR1-CTL in peripheral blood from patients with breast cancer and melanoma. Together, our data identify cross-presentation as a novel mechanism through which cells that lack endogenous expression of an Ag become susceptible to therapies that target cross-presented Ags and suggest PR1 as a broadly expressed tumor Ag.
authors.affiliation: Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. galatras@mdanderson.org
authors.forename: Gheath
authors.initials: G
authors.lastname: Alatrash
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Mittendorf
authors.forename: Anna
authors.initials: A
authors.lastname: Sergeeva
authors.forename: Pariya
authors.initials: P
authors.lastname: Sukhumalchandra
authors.forename: Na
authors.initials: N
authors.lastname: Qiao
authors.forename: Mao
authors.initials: M
authors.lastname: Zhang
authors.forename: Lisa S
authors.initials: LS
authors.lastname: St John
authors.forename: Kathryn
authors.initials: K
authors.lastname: Ruisaard
authors.forename: Christine E
authors.initials: CE
authors.lastname: Haugen
authors.forename: Zein
authors.initials: Z
authors.lastname: Al-Atrache
authors.forename: Haroon
authors.initials: H
authors.lastname: Jakher
authors.forename: Anne V
authors.initials: AV
authors.lastname: Philips
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Ding
authors.forename: Jie Qing
authors.initials: JQ
authors.lastname: Chen
authors.forename: Yun
authors.initials: Y
authors.lastname: Wu
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Patenia
authors.forename: Chantale
authors.initials: C
authors.lastname: Bernatchez
authors.forename: Luis M
authors.initials: LM
authors.lastname: Vence
authors.forename: Laszlo G
authors.initials: LG
authors.lastname: Radvanyi
authors.forename: Patrick
authors.initials: P
authors.lastname: Hwu
authors.forename: Karen
authors.initials: K
authors.lastname: Clise-Dwyer
authors.forename: Qing
authors.initials: Q
authors.lastname: Ma
authors.forename: Sijie
authors.initials: S
authors.lastname: Lu
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Molldrem
mesh_terms: D000906:Antibodies / Q000494:pharmacology; D000938:Antigen-Presenting Cells / Q000187:drug effects / Q000276:immunology; D000951:Antigens, Neoplasm / Q000276:immunology* / Q000378:metabolism; D001943:Breast Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D045142:Cross-Priming; D005260:Female; D015789:HLA-A2 Antigen / Q000276:immunology; D006801:Humans; D007167:Immunotherapy; D019272:Leukocyte Elastase / Q000737:chemistry / Q000276:immunology*; D008545:Melanoma / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D058990:Molecular Targeted Therapy; D053146:Myeloblastin / Q000737:chemistry / Q000276:immunology*; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology; D012878:Skin Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014407:Tumor Cells, Cultured
chemical_list: D000906:Antibodies; D000951:Antigens, Neoplasm; D015789:HLA-A2 Antigen; D010446:Peptide Fragments; D019272:Leukocyte Elastase; D053146:Myeloblastin