title: Targeting ALDH(bright) human carcinoma-initiating cells with ALDH1A1-specific CD8⁺ T cells.
abstract: OBJECTIVE
  Cancer-initiating cells (CIC) are considered to represent the subpopulation of tumor cells that is resistant to conventional cancer treatments, highly tumorigenic in immunodeficient mice, and responsible for tumor recurrence and metastasis. Based on an elevated aldehyde dehydrogenase (ALDH) activity attributable to ALDH1/3 isoforms, ALDH(bright) cells have been identified and isolated from tumors and shown to have characteristics of CIC. The ALDH1A1 isoform was previously identified as a tumor antigen recognized by CD8(+) T cells. This study examines the ability of ALDH1A1-specific CD8(+) T cells to eliminate ALDH(bright) cells and control tumor growth and metastases.
  
  
  METHODS
  ALDH(bright) cells were isolated by flow cytometry using ALDEFLUOR from HLA-A2(+) human head and neck, breast, and pancreas carcinoma cell lines and tested for their tumorigenicity in immunodeficient mice. ALDH1A1-specific CD8(+) T cells were generated in vitro and tested for their ability to eliminate CICs in vitro and in vivo by adoptive transfer to immunodeficient mice bearing human tumor xenografts.
  
  
  RESULTS
  ALDH(bright) cells isolated by flow cytometry from HLA-A2(+) breast, head and neck, and pancreas carcinoma cell lines at low numbers (500 cells) were tumorigenic in immunodeficient mice. ALDH(bright) cells present in these cell lines, xenografts, or surgically removed lesions were recognized by ALDH1A1-specific CD8(+) T cells in vitro. Adoptive therapy with ALDH1A1-specific CD8(+) T cells eliminated ALDH(bright) cells, inhibited tumor growth and metastases, or prolonged survival of xenograft-bearing immunodeficient mice.
  
  
  CONCLUSIONS
  The results of this translational study strongly support the potential of ALDH1A1-based immunotherapy to selectively target CICs in human cancer.
authors.affiliation: Division of Basic Research, University of Pittsburgh Cancer Institute, Hillman Cancer Center, Pittsburgh, Pennsylvania 15213, USA.
authors.forename: Carmen
authors.initials: C
authors.lastname: Visus
authors.forename: Yangyang
authors.initials: Y
authors.lastname: Wang
authors.forename: Antonio
authors.initials: A
authors.lastname: Lozano-Leon
authors.forename: Robert L
authors.initials: RL
authors.lastname: Ferris
authors.forename: Susan
authors.initials: S
authors.lastname: Silver
authors.forename: Miroslaw J
authors.initials: MJ
authors.lastname: Szczepanski
authors.forename: Randall E
authors.initials: RE
authors.lastname: Brand
authors.forename: Cristina R
authors.initials: CR
authors.lastname: Ferrone
authors.forename: Theresa L
authors.initials: TL
authors.lastname: Whiteside
authors.forename: Soldano
authors.initials: S
authors.lastname: Ferrone
authors.forename: Albert B
authors.initials: AB
authors.lastname: DeLeo
authors.forename: Xinhui
authors.initials: X
authors.lastname: Wang
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000276:immunology / Q000378:metabolism*; D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D016219:Immunotherapy, Adoptive; D007527:Isoenzymes / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000628:therapy*; D014411:Neoplastic Stem Cells / Q000276:immunology* / Q000378:metabolism; D050697:Retinal Dehydrogenase / Q000276:immunology* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D007527:Isoenzymes; D000080924:Aldehyde Dehydrogenase 1 Family; D000444:Aldehyde Dehydrogenase; C510223:ALDH1A1 protein, human; C515028:ALDH1A1 protein, mouse; D050697:Retinal Dehydrogenase