Chronic Myeloid Leukemia (CML) Cells Express Tumor Associated Antigens Eliciting Specific CD8+ T Cell Responses Despite of Deficient Expression of Costimulatory Molecules.

Specific immunotherapies for CML patients targeting T cell antigens might eliminate residual CML cells after therapy with imatinib or chemotherapy and might enhance a specific graft versus leukemia effect after allogeneic stem cell transplantation without aggravating the graft versus host disease. However, for effective specific immunotherapies in CML, extended studies on the expression, the function and the immunology of leukemia-associated antigens (LAAs) and on the LAA presentation by leukemia cells are required.

Here, we investigated on expression and functional aspects of tumor/leukemia-associated antigens (TAAs/LAAs) in CML. Several LAAs are expressed and are therefore candidate structures for specific immunotherapies: bcr-abl (100%), G250 (24%), hTERT (53%), MPP11 (91%), NEWREN60 (94%), PRAME (62%), Proteinase3 (71%), RHAMM/CD168 (83%) and WT1 (53%), but not BAGE, MAGE-A1, SSX2 or NY-ESO-1. The expression of LAAs varied according to leukocyte subsets and the expression of RHAMM/CD168, Proteinase3 and PRAME was upregulated in accelerated phase and blast crisis. Quantitative expression of several TAAs/LAAs correlated with the clinical course. In flow cytometry, CD34+ CML progenitor cells typed positive for HLA-molecules, but were deficient for CD40, CD80, CD83 and CD86. This lack of costimulatory molecules might constitute a tumor escape mechanism. However, RHAMM/CD168-R3-specific T cell responses were demonstrated by ELISPOT analysis and specific lysis of R3-peptide pulsed T2 cells in chromium-51 release assays. These CD8+ cells could be phenotyped as CCR7-CD27-CD45RA+ early effector T cells by tetramer staining. In conclusion, several LAAs are expressed in CML and are therefore candidate structures for specific immunotherapies. CML progenitor cells express HLA-molecules, but lack costimulatory molecules. However, as CML patients show RHAMM/CD168-R3-specific early effector T cells, peptide vaccination might be therefore a promising approach to enhance specific immune responses in CML.