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

Abstract

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.

• Authors: 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
• Journal: Haematologica (Haematologica) Vol. 95 Issue 3 Pg. 485-93 (Mar 2010) ISSN: 1592-8721 [Electronic] Italy
• PMID: 19903675 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, Differentiation, B-Lymphocyte
• HLA-DR Antigens
• Histocompatibility Antigens Class II
• RNA, Small Interfering
• invariant chain

Topics

• Adolescent
• Adult
• Aged
• Aged, 80 and over
• Antigen Presentation
• Antigens, Differentiation, B-Lymphocyte (chemistry, genetics, metabolism)
• Blast Crisis
• CD4-Positive T-Lymphocytes (immunology)
• Female
• HLA-DR Antigens (immunology)
• Histocompatibility Antigens Class II (chemistry, genetics, metabolism)
• Humans
• Leukemia, Myeloid, Acute (immunology, pathology)
• Lymphocyte Activation
• Male
• Middle Aged
• Prognosis
• RNA, Small Interfering (pharmacology)
• Tumor Cells, Cultured
• Young Adult