title: Human Leukocyte Antigen-Presented Macrophage Migration Inhibitory Factor Is a Surface Biomarker and Potential Therapeutic Target for Ovarian Cancer.
abstract: T cells recognize cancer cells via HLA/peptide complexes, and when disease overtakes these immune mechanisms, immunotherapy can exogenously target these same HLA/peptide surface markers. We previously identified an HLA-A2-presented peptide derived from macrophage migration inhibitory factor (MIF) and generated antibody RL21A against this HLA-A2/MIF complex. The objective of the current study was to assess the potential for targeting the HLA-A2/MIF complex in ovarian cancer. First, MIF peptide FLSELTQQL was eluted from the HLA-A2 of the human cancerous ovarian cell lines SKOV3, A2780, OV90, and FHIOSE118hi and detected by mass spectrometry. By flow cytometry, RL21A was shown to specifically stain these four cell lines in the context of HLA-A2. Next, partially matched HLA-A*02:01+ ovarian cancer (n = 27) and normal fallopian tube (n = 24) tissues were stained with RL21A by immunohistochemistry to assess differential HLA-A2/MIF complex expression. Ovarian tumor tissues revealed significantly increased RL21A staining compared with normal fallopian tube epithelium (P < 0.0001), with minimal staining of normal stroma and blood vessels (P < 0.0001 and P < 0.001 compared with tumor cells) suggesting a therapeutic window. We then demonstrated the anticancer activity of toxin-bound RL21A via the dose-dependent killing of ovarian cancer cells. In summary, MIF-derived peptide FLSELTQQL is HLA-A2-presented and recognized by RL21A on ovarian cancer cell lines and patient tumor tissues, and targeting of this HLA-A2/MIF complex with toxin-bound RL21A can induce ovarian cancer cell death. These results suggest that the HLA-A2/MIF complex should be further explored as a cell-surface target for ovarian cancer immunotherapy.
authors.affiliation: Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Patterson
authors.affiliation: Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
authors.forename: Saghar
authors.initials: S
authors.lastname: Kaabinejadian
authors.affiliation: Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. Pure MHC LLC, Oklahoma City, Oklahoma.
authors.forename: Curtis P
authors.initials: CP
authors.lastname: McMurtrey
authors.affiliation: Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
authors.forename: Wilfried
authors.initials: W
authors.lastname: Bardet
authors.affiliation: Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
authors.forename: Ken W
authors.initials: KW
authors.lastname: Jackson
authors.affiliation: Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
authors.forename: Rosemary E
authors.initials: RE
authors.lastname: Zuna
authors.affiliation: Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
authors.forename: Sanam
authors.initials: S
authors.lastname: Husain
authors.affiliation: Viventia Bio Inc., Winnipeg, Manitoba, Canada.
authors.forename: Gregory P
authors.initials: GP
authors.lastname: Adams
authors.affiliation: Viventia Bio Inc., Winnipeg, Manitoba, Canada.
authors.forename: Glen
authors.initials: G
authors.lastname: MacDonald
authors.affiliation: Viventia Bio Inc., Winnipeg, Manitoba, Canada.
authors.forename: Rachelle L
authors.initials: RL
authors.lastname: Dillon
authors.affiliation: Department of Immunotherapeutics and Biotechnology, Texas Tech University Health Sciences Center, Abilene, Texas.
authors.forename: Harold
authors.initials: H
authors.lastname: Ames
authors.affiliation: Pure MHC LLC, Oklahoma City, Oklahoma.
authors.forename: Rico
authors.initials: R
authors.lastname: Buchli
authors.affiliation: Department of Immunotherapeutics and Biotechnology, Texas Tech University Health Sciences Center, Abilene, Texas.
authors.forename: Oriana E
authors.initials: OE
authors.lastname: Hawkins
authors.affiliation: Department of Immunotherapeutics and Biotechnology, Texas Tech University Health Sciences Center, Abilene, Texas.
authors.forename: Jon A
authors.initials: JA
authors.lastname: Weidanz
authors.affiliation: Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. Pure MHC LLC, Oklahoma City, Oklahoma. William-Hildebrand@ouhsc.edu.
authors.forename: William H
authors.initials: WH
authors.lastname: Hildebrand
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use; D000915:Antibody Affinity; D000918:Antibody Specificity; D014408:Biomarkers, Tumor / Q000378:metabolism*; D045744:Cell Line, Tumor; D005260:Female; D015789:HLA-A2 Antigen / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000378:metabolism*; D008263:Macrophage Migration-Inhibitory Factors / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000473:pathology; D010455:Peptides / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D014408:Biomarkers, Tumor; D015789:HLA-A2 Antigen; D008263:Macrophage Migration-Inhibitory Factors; D010455:Peptides; D019746:Intramolecular Oxidoreductases; C515598:MIF protein, human