RHAMM/HMMR (CD168) is not an ideal target antigen for immunotherapy of acute myeloid leukemia
Sylvia Snauwaert,
Stijn Vanhee,
Glenn Goetgeluk,
Greet Verstichel,
Yasmine Van Caeneghem,
Imke Velghe,
Jan Philippé,
Zwi N. Berneman,
Jean Plum,
Tom Taghon,
Georges Leclercq,
Kris Thielemans,
Tessa Kerre,
Bart Vandekerckhove
Affiliations
Sylvia Snauwaert
Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, Ghent University Hospital, Ghent
Stijn Vanhee
Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, Ghent University Hospital, Ghent
Glenn Goetgeluk
Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, Ghent University Hospital, Ghent
Greet Verstichel
Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, Ghent University Hospital, Ghent
Yasmine Van Caeneghem
Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, Ghent University Hospital, Ghent
Imke Velghe
Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, Ghent University Hospital, Ghent
Jan Philippé
Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, Ghent University Hospital, Ghent
Zwi N. Berneman
Laboratory of Experimental Hematology, Antwerp University Hospital (UZA), University of Antwerp, Antwerp
Jean Plum
Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, Ghent University Hospital, Ghent
Tom Taghon
Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, Ghent University Hospital, Ghent
Georges Leclercq
Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, Ghent University Hospital, Ghent
Kris Thielemans
Laboratory of Molecular & Cellular Therapy of the Department of Physiology and Immunology, Free University Brussels (VUB), Brussels University Hospital, Brussels, Belgium
Tessa Kerre
Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, Ghent University Hospital, Ghent
Bart Vandekerckhove
Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, Ghent University Hospital, Ghent
Background Criteria for good candidate antigens for immunotherapy of acute myeloid leukemia are high expression on leukemic stem cells in the majority of patients with acute myeloid leukemia and low or no expression in vital tissues. It was shown in vaccination trials that Receptor for Hyaluronic Acid Mediated Motility (RHAMM/HMMR) generates cellular immune responses in patients with acute myeloid leukemia and that these responses correlate with clinical benefit. It is not clear however whether this response actually targets the leukemic stem cell, especially since it was reported that RHAMM is expressed maximally during the G2/M phase of the cell cycle. In addition, tumor specificity of RHAMM expression remains relatively unexplored.Design and Methods Blood, leukapheresis and bone marrow samples were collected from both acute myeloid leukemia patients and healthy controls. RHAMM expression was assessed at protein and mRNA levels on various sorted populations, either fresh or after manipulation.Results High levels of RHAMM were expressed by CD34+CD38+ and CD34- acute myeloid leukemia blasts. However, only baseline expression of RHAMM was measured in CD34+CD38- leukemic stem cells, and was not different from that in CD34+CD38- hematopoietic stem cells from healthy controls. RHAMM was significantly up-regulated in CD34+ cells from healthy donors during in vitro expansion and during in vivo engraftment. Finally, we demonstrated an explicit increase in the expression level of RHAMM after in vitro activation of T cells.Conclusions RHAMM does not fulfill the criteria of an ideal target antigen for immunotherapy of acute myeloid leukemia. RHAMM expression in leukemic stem cells does not differ significantly from the expression in hematopoietic stem cells from healthy controls. RHAMM expression in proliferating CD34+ cells of healthy donors and activated T cells further compromises RHAMM-specific T-cell-mediated immunotherapy.
