Haematologica (Mar 2010)

Class II-associated invariant chain peptide down-modulation enhances the immunogenicity of myeloid leukemic blasts resulting in increased CD4+ T-cell responses

  • Marvin M. van Luijn,
  • Martine E.D. Chamuleau,
  • James A. Thompson,
  • Suzanne Ostrand-Rosenberg,
  • Theresia M. Westers,
  • Yuri Souwer,
  • Gert J. Ossenkoppele,
  • S. Marieke van Ham,
  • Arjan A. van de Loosdrecht

DOI
https://doi.org/10.3324/haematol.2009.010595
Journal volume & issue
Vol. 95, no. 3

Abstract

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Background Disease recurrence in patients with acute myeloid leukemia may be partially explained by the escape of leukemic blasts from CD4+ T-cell recognition. The current study investigates the role of aberrant HLA class II antigen presentation on leukemic blasts by determining both the clinical and functional impact of the class II-associated invariant chain peptide (CLIP).Design and Methods The levels of expression of CLIP and HLA-DR on blood and bone marrow samples from 207 patients with acute myeloid leukemia were correlated with clinical outcome. Irradiated CLIP− and CLIP+ leukemic blasts were compared for their ability to induce CD4+ T cells during mixed leukocyte reactions. To discriminate between these blasts, we down-modulated CLIP expression on myeloid leukemic cell lines by RNA interference of the invariant chain, a chaperone protein critically involved in HLA-DR processing, and performed flow cytometric sorting for their isolation from primary acute myeloid leukemia samples.Results We found that patients with leukemic blasts characterized by a high amount of HLA-DR occupied by CLIP (relative amount of CLIP) had a significantly shortened disease-free survival. The clear reductions in amount of HLA-DR occupied by CLIP on blasts of the THP-1 and Kasumi-1 myeloid leukemic cell lines after treatment with invariant chain short interfering RNA resulted in enhanced rates of allogeneic CD4+ T-cell proliferation. Similar findings were obtained in an autologous setting, in which there were strong increases in proliferation of remission CD4+ T cells stimulated with CLIP−-sorted leukemic blasts from HLA-DR+ acute myeloid leukemia patients, in contrast to CLIP+-sorted leukemic blasts from the same patients.Conclusions These data highlight the relevance of CLIP expression on leukemic blasts and the potential of CLIP as a target for immunomodulatory strategies to enhance HLA class II antigen presentation and CD4+ T-cell reactivity in acute myeloid leukemia.