TY - JOUR
T1 - Class II-associated invariant chain peptide down-modulation enhances the immunogenicity of myeloid leukemic blasts resulting in increased CD4+ T-cell responses
AU - van Luijn, Marvin M.
AU - Chamuleau, Martine E. D.
AU - Thompson, James A.
AU - Ostrand-Rosenberg, Suzanne
AU - Westers, Theresia M.
AU - Souwer, Yuri
AU - Ossenkoppele, Gert J.
AU - van Ham, S. Marieke
AU - van de Loosdrecht, Arjan A.
PY - 2010
Y1 - 2010
N2 - 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). 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. 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. 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
AB - 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). 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. 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. 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
U2 - https://doi.org/10.3324/haemato1.2009.010595
DO - https://doi.org/10.3324/haemato1.2009.010595
M3 - Article
C2 - 19903675
SN - 0390-6078
VL - 95
SP - 485
EP - 493
JO - Haematologica
JF - Haematologica
IS - 3
ER -