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MDM2 is recognized as a tumor-associated antigen in chronic lymphocytic leukemia by CD8+ autologous T lymphocytes.

Abstract：

OBJECTIVE:Tumor-associated antigens (TAA) are the basis for antigen-specific immunotherapy. The human homolog of the murine double-minute 2 oncoprotein (MDM2) is a putative TAA because it is overexpressed in several malignancies, including chronic lymphocytic leukemia (CLL) cells compared with normal B lymphocytes. PATIENTS AND METHODS:Autologous, MDM2-specific human leukocyte antigen (HLA)-A2-restricted T cells were identified using interferon (IFN)-gamma-ELISPOT assays and HLA-A2/dimer-peptide staining after 4 weeks of in vitro culture. RESULTS:Using native CLL cells as antigen-presenting cells (APCs), we demonstrate the generation of MDM2-specific T cells in 7/12 CLL patients that recognized specifically the MDM2-derived peptide MDM2(81-88) bound to HLA-A2-dimers while they were inactive against an unrelated MAGE-3 peptide (p = 0.002). After 4 weeks, up to 32.3% of the expanded CD8(+) T cells specifically recognized MDM2(81-88) by HLA-A2-dimer/peptide staining and up to 0.9% of all T cells expanded reacted specifically against this MDM2-derived peptide in the IFN-gamma-ELISPOT assay. If T cells were not expandable using native CLL cells as APC, leukemic cells were stimulated with CD40-ligand to increase the antigen-presenting capacity. This resulted in successful generation of MDM2-specific T cells in three of five remaining cases tested. Additionally, the factor that correlated best with successful generation of antigen-specific T cells in CLL patients was the ability of APCs to secrete IFN-gamma upon stimulation. CONCLUSION:In summary, MDM2(81-88) was shown for the first time in humans to elicit a functional autologous immune response. MDM2 was demonstrated to be naturally processed and presented as TAA in primary human CLL cells enabling expansion of functional autologous tumor-specific T cells.

journal_name

Exp Hematol

journal_title

Experimental hematology

authors

Mayr C,Bund D,Schlee M,Bamberger M,Kofler DM,Hallek M,Wendtner CM

doi

10.1016/j.exphem.2005.09.016

keywords:

subject

Has Abstract

pub_date

2006-01-01 00:00:00

pages

44-53

issue

eissn

0301-472X

issn

1873-2399

pii

S0301-472X(05)00467-4

journal_volume

pub_type

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MDM2 is recognized as a tumor-associated antigen in chronic lymphocytic leukemia by CD8+ autologous T lymphocytes.