Identification and characterization of epitopes of the receptor for hyaluronic acid-mediated motility (RHAMM/CD168) recognized by CD8+ T cells of HLA-A2-positive patients with acute myeloid leukemia.
The receptor for hyaluronic acid-mediated motility (RHAMM/CD168) has been described as a leukemia-associated antigen. To define T-cell epitopes of RHAMM/CD168 toward specific immunotherapies for acute myeloid leukemia (AML), 10 potential HLA-A2-binding RHAMM/CD168 peptides (R1 to R10) were synthesized based on computer algorithms and screened by enzyme-linked immunospot (ELISPOT) analysis using CD8+ T cells isolated from peripheral blood (PB) of patients with AML and healthy donors. We found that CD8+ cells from 7 of 13 (54%) patients with AML presensitized with peptides R3 (ILSLELMKL) or R5 (SLEENIVIL) specifically recognized T2 cells pulsed with R3 (39%) or R5 (15%) peptide. In contrast, only 4 of 21 (19%) healthy volunteers had CD8+ cells reactive with R3- or R5-pulsed T2 cells after presensitization. The presence of R3 peptide-specific effector T cells in the peripheral blood of patients with AML could be confirmed by staining as HLA-A2/R3 peptide tetramer+ CCR7-CD45RA+ cells. In chromium-51 release assays, peptide-primed CD8+ T cells from patients with AML were able to lyse RHAMM/CD168 peptide-pulsed T2 cells, AML blasts, and dendritic cells generated thereof (AML DCs). Transfection of COS7 cells with RHAMM/CD168 cDNA revealed that peptides R3 and R5 are naturally processed epitopes of RHAMM/CD168 that are presented in an HLA-A2-restricted manner. In summary, RHAMM/CD168 is a promising target for immunotherapies in patients with AML, and we have therefore initiated a clinical vaccination trial with R3 peptide. Because RHAMM/CD168 is also expressed in various other hematologic malignancies and solid tumors, vaccines targeting this antigen may have even wider application.
Greiner
Jochen
J
Third Department of Internal Medicine, University of Ulm, Robert-Koch-Str 8, 89081 Ulm, Germany.
Li
Li
L
Ringhoffer
Mark
M
Barth
Thomas F E
TF
Giannopoulos
Krzysztof
K
Guillaume
Phillipe
P
Ritter
Gerd
G
Wiesneth
Markus
M
Döhner
Hartmut
H
Schmitt
Michael
M
D000208:Acute Disease; D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D000951:Antigens, Neoplasm / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003602:Cytotoxicity, Immunologic; D018604:Epitope Mapping; D018984:Epitopes, T-Lymphocyte; D016326:Extracellular Matrix Proteins / Q000276:immunology*; D005260:Female; D015789:HLA-A2 Antigen; D006801:Humans; D018960:Hyaluronan Receptors / Q000276:immunology*; D007167:Immunotherapy; D007951:Leukemia, Myeloid / Q000276:immunology* / Q000628:therapy; D008297:Male; D008875:Middle Aged; D010455:Peptides / Q000138:chemical synthesis / Q000276:immunology
D000951:Antigens, Neoplasm; D018984:Epitopes, T-Lymphocyte; D016326:Extracellular Matrix Proteins; D015789:HLA-A2 Antigen; D018960:Hyaluronan Receptors; D010455:Peptides; C098946:hyaluronan-mediated motility receptor