Myeloid leukemic progenitor cells can be specifically targeted by minor histocompatibility antigen LRH-1–reactive cytotoxic T cells

Author:

Norde Wieger J.1,Overes Ingrid M.1,Maas Frans1,Fredrix Hanny1,Vos Johanna C. M.1,Kester Michel G. D.2,van der Voort Robbert1,Jedema Inge2,Falkenburg J. H. Frederik2,Schattenberg Anton V.3,de Witte Theo M.13,Dolstra Harry1

Affiliation:

1. Central Hematology Laboratory, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen;

2. Department of Hematology, Leiden University Medical Center, Leiden; and

3. Department of Hematology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

Abstract

Abstract CD8+ T cells recognizing minor histocompatibility antigens (MiHAs) 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 (CTLs) isolated from 2 different patients efficiently target LRH-1–positive leukemic CD34+ progenitor cells from both CML and AML patients, whereas 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 antiapoptotic XIAP could be overcome by IFN-γ prestimulation 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.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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