Submitted April 23, 2008
Accepted November 16, 2008
Myeloid leukemic progenitor cells can be specifically targeted by minor histocompatibility antigen LRH-1-reactive cytotoxic T cells
Wieger J. Norde, Ingrid M. Overes, Frans Maas, Hanny Fredrix, Johanna C.M. Vos, Michel G.D. Kester, Robbert van der Voort, Inge Jedema, J.H. Frederik Falkenburg, Anton V. Schattenberg, Theo M. de Witte, and Harry Dolstra*
Central Hematology Laboratory, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands
Department of Hematology, Leiden University Medical Center, Leiden, Netherlands
Department of Hematology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands
* Corresponding author; email: h.dolstra{at}chl.umcn.nl.
CD8+ T cells recognizing minor histocompatibility antigens (MiHA) on leukemic stem and progenitor cells play a pivotal role in effective graft-versus-leukemia reactivity after allogeneic stem cell transplantation (SCT). Previously, we identified a hematopoiesis-restricted MiHA, designated LRH-1, which is presented by HLA-B7 and encoded by the P2X5 purinergic receptor gene. We found that P2X5 is significantly expressed in CD34+ leukemic subpopulations from chronic myeloid leukemia (CML) and acute myeloid leukemia (AML) patients. Here, we demonstrate that LRH-1-specific CD8+ T cell responses are frequently induced in myeloid leukemia patients following donor lymphocyte infusions. Patients with high percentages of circulating LRH-1-specific CD8+ T cells had no or only mild graft-versus-host disease. Functional analysis showed that LRH-1-specific cytotoxic T lymphocytes (CTL) isolated from two different patients efficiently target LRH-1-positive leukemic CD34+ progenitor cells from both CML and AML patients, while mature CML cells are only marginally lysed due to down-regulation of P2X5. Furthermore, we observed that relative resistance to LRH-1 CTL-mediated cell death due to elevated levels of anti-apoptotic XIAP could be overcome by IFN-
pre-stimulation and increased CTL-target ratios. These findings provide a rationale for use of LRH-1 as immunotherapeutic target antigen to treat residual or persisting myeloid malignancies after allogeneic SCT.
