Detection and functional analysis of CD8+ T cells specific for PRAME: a target for T-cell therapy

Marieke Griffioen, Jan H. Kessler, Martina Borghi, Ronald A. van Soest, Caroline E. van der Minne, Jan Nouta, Sjoerd H. van der Burg, Jan Paul Medema, Peter I. Schrier, J. H. Frederik Falkenburg, Susanne Osanto, Cornelis J. M. Melief

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

PURPOSE: Preferentially expressed antigen on melanomas (PRAME) is an interesting antigen for T-cell therapy because it is frequently expressed in melanomas (95%) and other tumor types. Moreover, due to its role in oncogenic transformation, PRAME-negative tumor cells are not expected to easily arise and escape from T-cell immunity. The purpose of this study is to investigate the usefulness of PRAME as target for anticancer T-cell therapies. EXPERIMENTAL DESIGN: HLA-A*0201-subtyped healthy individuals and advanced melanoma patients were screened for CD8+ T cells directed against previously identified HLA-A*0201-binding PRAME peptides by IFN-gamma enzyme-linked immunosorbent spot assays and tetramer staining. PRAME-specific T-cell clones were isolated and tested for recognition of melanoma and acute lymphoid leukemia (ALL) cell lines. PRAME mRNA expression was determined by quantitative real-time reverse transcription-PCR. RESULTS: In 30% to 40% of healthy individuals and patients, PRA(100-108)-specific CD8+ T cells were detected both after in vitro stimulation and directly ex vivo after isolation by magnetic microbeads. Although CD45RA- memory PRA(100-108)-specific T cells were found in some individuals, the majority of PRA(100-108)-tetramer+ T cells expressed CD45RA, suggesting a naive phenotype. PRA(100-108)-tetramer+ T-cell clones were shown to recognize and lyse HLA-A*0201+ and PRAME+ melanoma but not ALL cell lines. Quantitative real-time reverse transcription-PCR showed significantly lower PRAME mRNA levels in ALL than in melanoma cell lines, suggesting that PRAME expression in ALL is below the recognition threshold of our PRA(100-108)-tetramer+ T cells. CONCLUSION: These data support the usefulness of PRAME and in particular the PRA(100-108) epitope as target for T-cell therapy of PRAME-overexpressing cancers
Original languageEnglish
Pages (from-to)3130-3136
JournalClinical cancer research
Volume12
Issue number10
DOIs
Publication statusPublished - 2006

Cite this