CTL recognition of a novel HLA-A*0201-binding peptide derived from glioblastoma multiforme tumor cells |
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Authors: | Cheryl E Myers Paul Hanavan Kwasi Antwi Daruka Mahadevan A Jamal Nadeem Laurence Cooke Adrienne C Scheck Zachary Laughrey Douglas F Lake |
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Institution: | (1) School of Life Sciences, Arizona State University, Tempe, AZ 85287, USA;(2) Department of Chemistry and Biochemistry, Arizona State University, Tempe, AZ 85287, USA;(3) Department of Medicine, Arizona Cancer Center, University of Arizona, Tucson, AZ 85724, USA;(4) Barrow Neurological Institute of SJHMC, Phoenix, AZ 85013, USA; |
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Abstract: | Genetic instability of tumor cells can result in translation of proteins that are out of frame, resulting in expression of
neopeptides. These neopeptides are not self-proteins and therefore should be immunogenic. By eluting peptides from human glioblastoma
multiforme (GBM) tumor cell surfaces and subjecting them to tandem mass spectrometry, we identified a novel peptide (KLWGLTPKVTPS)
corresponding to a frameshift in the 3′ beta-hydroxysteroid dehydrogenase type 7 (HSD3B7) gene. HLA-binding algorithms predicted
that a 9-amino acid sequence embedded in this peptide would bind to HLA-A*0201. We confirmed this prediction using an HLA-A*0201
refolding assay followed by live cell relative affinity assays, but also showed that the 12-mer binds to HLA-A*0201. Based
on the 9-mer sequence, optimized peptide ligands (OPL) were designed and tested for their affinities to HLA-A*0201 and their
abilities to elicit anti-peptide and CTL capable of killing GBM in vitro. Wild-type peptides as well as OPL induced anti-peptide
CTL as measured by IFN-γ ELISPOTS. These CTL also killed GBM tumor cells in chromium-51 release assays. This study reports
a new CTL target in GBM and further substantiates the concept that rational design and testing of multiple peptides for the
same T-cell epitope elicits a broader response among different individuals than single peptide immunization. |
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