Increased PRAME antigen-specific killing of malignant cell lines by low avidity CTL clones, following treatment with 5-Aza-2'-Deoxycytidine.

Abstract

The cancer testis antigen Preferentially Expressed Antigen of Melanoma (PRAME) is overexpressed in many solid tumours and haematological malignancies whilst showing minimal expression in normal tissues and is therefore a promising target for immunotherapy. HLA-A0201-restricted peptide epitopes from PRAME have previously been identified as potential immunogens to drive antigen-specific autologous CTL responses, capable of lysing PRAME expressing tumour cells. CTL lines, from 13 normal donors and 10 melanoma patients, all of whom were HLA-A0201 positive, were generated against the PRAME peptide epitope PRA(100-108). Specific killing activity against PRA(100-108) peptide-pulsed targets was weak compared with CTL lines directed against known immunodominant peptides. Moreover, limiting dilution cloning from selected PRAME-specific CTL lines resulted in the generation of a clone of only low to intermediate avidity. Addition of the demethylating agent 5-aza-2'-Deoxycytidine (DAC) increased PRAME expression in 7 out of 11 malignant cell lines including several B lineage leukaemia lines and also increased class I expression. Pre-treatment of target cells was associated with increased sensitivity to antigen-specific killing by the low avidity CTL. When CTL, as well as of the target cells, were treated, the antigen-specific killing was further augmented. Interestingly, one HLA-A0201-negative DAC-treated line (RAJI) showed increased sensitivity to killing by clones despite a failure of expression of PRAME or HLA-A0201. Together these data point to a general increased augmentation of cancer immunogenocity by DAC involving both antigen-specific and non-specific mechanisms.

• Authors: Mengyong Yan, Nourredine Himoudi, B Piku Basu, Rebecca Wallace, Edmund Poon, Stuart Adams, Fyeza Hasan, Shao-An Xue, Natalie Wilson, Angus Dalgleish, Owen Williams, John Anderson
• Journal: Cancer immunology, immunotherapy : CII (Cancer Immunol Immunother) Vol. 60 Issue 9 Pg. 1243-55 (Sep 2011) ISSN: 1432-0851 [Electronic] Germany
• PMID: 21553146 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, Neoplasm
• Antimetabolites, Antineoplastic
• HLA-A*02:01 antigen
• HLA-A2 Antigen
• PRAME protein, human
• Decitabine
• Azacitidine

Topics

• Antibody Affinity
• Antigens, Neoplasm (immunology, metabolism)
• Antimetabolites, Antineoplastic (pharmacology)
• Azacitidine (analogs & derivatives, pharmacology)
• Cell Line, Tumor
• Cytotoxicity, Immunologic (immunology)
• Decitabine
• HL-60 Cells
• HLA-A2 Antigen (immunology)
• Humans
• Immunotherapy, Adoptive (methods)
• K562 Cells
• Neoplasms (immunology, therapy)
• T-Lymphocytes, Cytotoxic (immunology)
• Transfection