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.
Luetkens
Tim
T
Department of Oncology and Hematology, Center of Oncology, Hamburg, Germany.
Schafhausen
Phillipe
P
Uhlich
Frederike
F
Stasche
Tim
T
Akbulak
Ruken
R
Bartels
Britta M
BM
Hildebrandt
York
Y
Gontarewicz
Arthur
A
Kobold
Sebastian
S
Meyer
Sabrina
S
Gordic
Maja
M
Bartels
Katrin
K
Lajmi
Nesrine
N
Cao
Yanran
Y
Kröger
Nicolaus
N
Bokemeyer
Carsten
C
Brümmendorf
Tim H
TH
Atanackovic
Djordje
D
D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm / Q000096:biosynthesis / Q000276:immunology*; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D001549:Benzamides; D000077209:Decitabine; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000276:immunology; D044127:Epigenesis, Genetic / Q000187:drug effects / Q000276:immunology*; D005260:Female; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D000068877:Imatinib Mesylate; D056724:Immunity, Humoral / Q000187:drug effects / Q000276:immunology*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism / Q000401:mortality; D008297:Male; D008875:Middle Aged; D018365:Neoplasm, Residual / Q000276:immunology / Q000378:metabolism; D010879:Piperazines / Q000627:therapeutic use; D011743:Pyrimidines / Q000627:therapeutic use
D000951:Antigens, Neoplasm; D000964:Antimetabolites, Antineoplastic; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000077209:Decitabine; D000068877:Imatinib Mesylate; D001374:Azacitidine