Mapping of novel peptides of WT-1 and presenting HLA alleles that induce epitope-specific HLA-restricted T cells with cytotoxic activity against WT-1(+) leukemias Journal Article

   

Authors:	Doubrovina, E.; Carpenter, T.; Pankov, D.; Selvakumar, A.; Hasan, A.; O'Reilly, R. J.
Article Title:	Mapping of novel peptides of WT-1 and presenting HLA alleles that induce epitope-specific HLA-restricted T cells with cytotoxic activity against WT-1(+) leukemias
Abstract:	The Wilms tumor protein (WT-1) is widely recognized as a tumor antigen that is expressed differentially by several malignancies. However, WT-1 peptides known to induce tumoricidal T cells are few. In the present study, we evaluated T-cell responses of 56 healthy donors to in vitro sensitization with autologous APCs loaded with a pool of overlapping 15-mer peptides spanning the sequence of WT-1. Thereafter, we mapped the WT-1 peptides eliciting responses in each individual, defined the immunogenic peptides, and identified their presenting HLA alleles. We report 41 previously unreported epitopes of WT-1: 5 presented by class II and 36 by class I alleles, including 10 that could be presented by more than 1 class I allele. IFNγ + T cells responding to 98% of the class I and 60% of the class II epitopes exhibited HLA-restricted cytotoxicity against peptide-loaded targets. T cells specific for 36 WT-1 peptides were evaluable for leukemocidal activity, of which 27 (75%) lysed WT-1 + leukemic targets sharing their restricting HLA allele. Each epitope identified induced T-cell responses in most donors sharing the epitopes' presenting allele; these responses often exceeded responses to flanking peptides predicted to be more immunogenic. This series of immunogenic epitopes of WT-1 should prove useful for immunotherapies targeting WT-1 + malignancies. © 2012 by The American Society of Hematology.
Keywords:	controlled study; protein expression; leukemia; unclassified drug; human cell; cd8 antigen; cd8+ t lymphocyte; allele; cancer immunotherapy; antineoplastic activity; cytotoxicity; in vitro study; drug screening; tumor antigen; antigen presentation; immune response; amino acid sequence; gamma interferon; immunogenicity; hla antigen class 2; cd4+ t lymphocyte; epitope mapping; epitope; cytotoxic t lymphocyte; hla antigen class 1; cytolysis; target cell; cd4 antigen; antigen presenting cell; peripheral blood mononuclear cell; sensitization; peptide mapping; peptide derivative; protein wt 1; pentadecapeptide; leukemocidal activity
Journal Title:	Blood
Volume:	120
Issue:	8
ISSN:	0006-4971
Publisher:	American Society of Hematology
Date Published:	2012-08-23
Start Page:	1633
End Page:	1646
Language:	English
DOI:	10.1182/blood-2011-11-394619
PROVIDER:	scopus
PMCID:	PMC3429306
PUBMED:	22623625
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-84865403847&partnerID=40&md5=cc2110bbc272b3ce003316614e387d51
Notes:	--- - "Cited By (since 1996): 1" - "Export Date: 1 October 2012" - "CODEN: BLOOA" - "Source: Scopus"

https://synapse.mskcc.org/synapse/works/has_related_data_chk/33725