Expression, epigenetic regulation, and humoral immunogenicity of cancer-testis antigens in chronic myeloid leukemia.

OBJECTIVE

Cancer-testis (CT) antigens represent attractive targets for tumor immunotherapy based on their tumor-restricted expression and immunogenicity. However, a broad picture of the expression of CT antigens and associated humoral immune responses in chronic myeloid leukemia (CML) is still missing.

METHODS

We screened CML cell lines and bone marrow (BM) samples from healthy donors by RT-PCR for the expression of 31 CT antigens before and after treatment with epigenetic agents. Expression of tumor-restricted antigens was further examined in 60 CML patients and humoral immune responses against 15 CT antigens were screened by ELISA.

RESULTS

In untreated cell lines we detected the expression of 17 CT antigens that were absent from normal BM. Expression of most antigens increased following demethylating treatment with 5'-Aza-2'-Deoxycytidine. In these samples, only PRAME was repeatedly detected and expression correlated with several clinicopathological parameters and decreased overall survival. We further show that a lower frequency of PRAME-positive samples during imatinib treatment was not caused by gene-specific downregulation. Analyzing the patients' antibody responses we found that the vast majority of patients lacked spontaneous immunity against CT antigens including PRAME.

CONCLUSIONS

CT antigen expression can be increased by the application of epigenetic agents and the expression of PRAME correlates with clinicopathological parameters and overall survival in patients with CML, but does not lead to humoral immune responses. PRAME-specific immunotherapy might represent a promising approach for the eradication of residual therapy-resistant leukemic cells due to its frequent expression and stability under imatinib treatment.