Class II-associated invariant chain peptide down-modulation enhances the immunogenicity of myeloid leukemic blasts resulting in increased CD4+ T-cell responses |
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| Authors: | Marvin M van Luijn Martine ED Chamuleau James A Thompson Suzanne Ostrand-Rosenberg Theresia M Westers Yuri Souwer Gert J Ossenkoppele S Marieke van Ham and Arjan A van de Loosdrecht |
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| Institution: | 1 Department of Hematology, VU Institute for Cancer and Immunology, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, The Netherlands;;2 Department of Immunopathology, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands and;3 Department of Biological Sciences, University of Maryland, Baltimore County, Baltimore, USA |
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| Abstract: | BackgroundDisease 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 MethodsThe 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.ResultsWe 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.ConclusionsThese 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. |
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| Keywords: | acute myeloid leukemia CLIP expression leukemic blasts |
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