title: Augmentation of anti-HLA-E antibodies with concomitant HLA-Ia reactivity in IFNγ-treated autologous melanoma cell vaccine recipients.
abstract: HLA-E expressed on the surface of melanoma cells and shed into circulation are known to inhibit killing of tumor cells by binding to CD94/NKGA2 receptors on cytotoxic T- and NKT cells. Interferon (IFN)-γ is known to promote HLA-E over-expression on the cell surface and shedding. The shed HLA-E heavy chain may expose cryptic epitopes to elicit antibodies (Abs). The anti-HLA-E Abs may bind to shed HLA-E or to the tumor cell surface to block its interaction with CTL/NKT cells. This is the basis for a melanoma cell vaccine that will generate anti-HLA-E Abs. The objective of this study was to characterize the antibody response and characterize the cross-reactivity of the antibodies produced in melanoma patients immunized with autologous melanoma cells treated with IFNγ. Anti-HLA-E murine mAbs and serum anti-HLA-E Abs in healthy individuals were known to react with HLA-Ia alleles, which is attributed to the presence of peptide sequences shared between HLA-E and HLA-Ia. Therefore, pre- and post-immune (weeks 4 and 24) serum Abs reacting to both HLA-E and HLA-Ia alleles were measured by multiplex Luminex®-based immunoassay. To ascertain whether the reactivity of the serum Abs to HLA-Ia was due to anti-HLA-E Abs, the shared-peptides were used to inhibit anti-HLA-E and HLA-Ia reactivities. The level of anti-HLA-E IgG in sera has increased post-immunization from its pre-immune level. Concomitantly, the HLA-Ia reactivity of the sera was also augmented. The reactivity of both anti-HLA-E Abs and HLA-Ia were inhibited by the shared-peptides. The HLA-Ia reactivity of the anti-HLA-E Abs in patients' sera is similar to the HLA-Ia reactivity of the anti-HLA-E mAbs and anti-HLA-E Abs in normal sera. The results establish the immunogenicity of HLA-E and also ascertain that the HLA-Ia reactivity of the anti-HLA-E Abs is due to shared-peptide epitopes.
authors.affiliation: Terasaki Foundation Laboratory, Los Angeles, CA 90064, USA. ravimh@terasakilab.org
authors.forename: Mepur H
authors.initials: MH
authors.lastname: Ravindranath
authors.forename: Senthamil R
authors.initials: SR
authors.lastname: Selvan
authors.forename: Paul I
authors.initials: PI
authors.lastname: Terasaki
mesh_terms: D001323:Autoantibodies / Q000097:blood / Q000276:immunology; D019496:Cancer Vaccines / Q000008:administration & dosage*; D005260:Female; D015395:Histocompatibility Antigens Class I / Q000097:blood / Q000276:immunology; D006801:Humans; D007114:Immunization; D007371:Interferon-gamma / Q000008:administration & dosage*; D008297:Male; D008545:Melanoma / Q000097:blood / Q000276:immunology / Q000628:therapy; D058950:Melanoma-Specific Antigens / Q000097:blood / Q000276:immunology; D013997:Time Factors; D000097625:HLA-E Antigens
chemical_list: D001323:Autoantibodies; D019496:Cancer Vaccines; D015395:Histocompatibility Antigens Class I; D007371:Interferon-gamma; D058950:Melanoma-Specific Antigens; D000097625:HLA-E Antigens; C573415:IFNG protein, human