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

Blood. 2005 Aug 1;106(3):938-45. doi: 10.1182/blood-2004-12-4787. Epub 2005 Apr 12.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • Adult
  • Aged
  • Amino Acid Sequence
  • Antigens, Neoplasm / immunology
  • CD8-Positive T-Lymphocytes / immunology*
  • Cytotoxicity, Immunologic
  • Epitope Mapping
  • Epitopes, T-Lymphocyte*
  • Extracellular Matrix Proteins / immunology*
  • Female
  • HLA-A2 Antigen*
  • Humans
  • Hyaluronan Receptors / immunology*
  • Immunotherapy
  • Leukemia, Myeloid / immunology*
  • Leukemia, Myeloid / therapy
  • Male
  • Middle Aged
  • Peptides / chemical synthesis
  • Peptides / immunology

Substances

  • Antigens, Neoplasm
  • Epitopes, T-Lymphocyte
  • Extracellular Matrix Proteins
  • HLA-A2 Antigen
  • Hyaluronan Receptors
  • Peptides
  • hyaluronan-mediated motility receptor