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


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.
van Luijn
Marvin M
MM
Department of Hematology, VU Institute for Cancer and Immunology, Cancer Center Amsterdam, VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands. m.luijn@vumc.nl
Chamuleau
Martine E D
ME
Thompson
James A
JA
Ostrand-Rosenberg
Suzanne
S
Westers
Theresia M
TM
Souwer
Yuri
Y
Ossenkoppele
Gert J
GJ
van Ham
S Marieke
SM
van de Loosdrecht
Arjan A
AA
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017951:Antigen Presentation; D000944:Antigens, Differentiation, B-Lymphocyte / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D001752:Blast Crisis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D005260:Female; D006684:HLA-DR Antigens / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000276:immunology* / Q000473:pathology; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D034741:RNA, Small Interfering / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D055815:Young Adult
D000944:Antigens, Differentiation, B-Lymphocyte; D006684:HLA-DR Antigens; D000949:Histocompatibility Antigens Class II; D034741:RNA, Small Interfering; C045084:invariant chain