An HLA-presented fragment of macrophage migration inhibitory factor is a therapeutic target for invasive breast cancer

• Published in: The Journal of immunology (1950) 2011-06, Vol.186 (11), p.6607-6616
• Main Authors: Hawkins, Oriana, Verma, Bhavna, Lightfoot, Stanley, Jain, Rinki, Rawat, Amit, McNair, Sandy, Caseltine, Shannon, Mojsilovic, Aleksandar, Gupta, Priyanka, Neethling, Francisca, Almanza, Othon, Dooley, William, Hildebrand, William, Weidanz, Jon
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Antibodies, Monoclonal - immunology; Antibodies, Monoclonal - therapeutic use; Antibody Affinity - immunology; Antibody Specificity - immunology; Apoptosis - drug effects; Apoptosis - immunology; Breast Neoplasms - drug therapy; Breast Neoplasms - immunology; Breast Neoplasms - pathology; Carcinoma, Ductal, Breast - drug therapy; Carcinoma, Ductal, Breast - immunology; Carcinoma, Ductal, Breast - pathology; Cell Line; Cell Line, Tumor; Cell Survival - drug effects; Cell Survival - immunology; Dose-Response Relationship, Drug; Female; HLA-A Antigens - immunology; HLA-A Antigens - metabolism; HLA-A2 Antigen; Humans; Kinetics; Macrophage Migration-Inhibitory Factors - chemistry; Macrophage Migration-Inhibitory Factors - immunology; Macrophage Migration-Inhibitory Factors - metabolism; Mice; Mice, Nude; Peptides - immunology; Peptides - metabolism; Prognosis; Protein Binding - immunology; Xenograft Model Antitumor Assays
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1003995

This report describes a novel HLA/peptide complex with potential prognostic and therapeutic roles for invasive breast cancer. Macrophage migration inhibitory factor (MIF) mediates inflammation and immunity, and MIF overexpression is observed in breast cancer. We hypothesized that the HLA class I of cancerous breast epithelial cells would present MIF-derived peptides. Consistent with this hypothesis, the peptide FLSELTQQL (MIF(19-27)) was eluted from the HLA-A*0201 (HLA-A2) of breast cancer cell lines. We posited that if this MIF(19-27)/HLA-A2 complex was exclusively found in invasive breast cancer, it could be a useful prognostic indicator. To assess the presentation of MIF peptides by the HLA of various cells and tissues, mice were immunized with the MIF(19-27)/HLA-A2 complex. The resulting mAb (RL21A) stained invasive ductal carcinoma (IDC) but not ductal carcinoma in situ, fibroadenoma, or normal breast tissues. RL21A did not stain WBCs (total WBCs) or normal tissues from deceased HLA-A2 donors, substantiating the tumor-specific nature of this MIF/HLA complex. As this MIF/HLA complex appeared specific to the surface of IDC, RL21A was tested as an immunotherapeutic for breast cancer in vitro and in vivo. In vitro, RL21A killed the MDA-MB-231 cell line via complement and induction of apoptosis. In an in vivo orthotopic mouse model, administration of RL21A reduced MDA-MB-231 and BT-20 tumor burden by 5-fold and by >2-fold, respectively. In summary, HLA-presented MIF peptides show promise as prognostic cell surface indicators for IDC and as targets for immunotherapeutic intervention.