Identification of the angiogenic endothelial-cell growth factor-1/thymidine phosphorylase as a potential target for immunotherapy of cancer.
Characterization of the antigens recognized by tumor-reactive T cells isolated from patients successfully treated with allogeneic HLA-matched hematopoietic stem cell transplantation (SCT) can lead to the identification of clinically relevant target molecules. We isolated tumor-reactive cytotoxic CD8(+) T-cell (CTL) clones from a patient successfully treated with donor lymphocyte infusion for relapsed multiple myeloma after allogeneic HLA-matched SCT. Using cDNA expression cloning, the target molecule of an HLA-B7-restricted CTL clone was identified. The CTL clone recognized a minor histocompatibility antigen produced by a single nucleotide polymorphism (SNP) in the angiogenic endothelial-cell growth factor-1 (ECGF1) gene also known as thymidine phosphorylase. The SNP leads to an Arg-to-His substitution in an alternatively translated peptide that is recognized by the CTL. The ECGF1 gene is predominantly expressed in hematopoietic cells, although low expression can also be detected in other tissues. The patient from whom this CTL clone was isolated had mild graft-versus-host disease despite high numbers of circulating ECGF-1-specific T cells as detected by tetramer staining. Because solid tumors expressing ECGF-1 could also be lysed by the CTL, ECGF-1 is an interesting target for immunotherapy of both hematologic and solid tumors.
Slager
Elisabeth H
EH
Department of Hematology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands. e.h.slager@lumc.nl
Honders
M Willy
MW
van der Meijden
Edith D
ED
van Luxemburg-Heijs
Simone A P
SA
Kloosterboer
Freke M
FM
Kester
Michel G D
MG
Jedema
Inge
I
Marijt
W A Erik
WA
Schaafsma
M Ron
MR
Willemze
Roel
R
Falkenburg
J H Frederik
JH
D019943:Amino Acid Substitution / Q000276:immunology*; D001483:Base Sequence; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology; D006086:Graft vs Host Disease / Q000235:genetics / Q000276:immunology; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000276:immunology; D006801:Humans; D007167:Immunotherapy; D017710:Lymphocyte Transfusion; D008969:Molecular Sequence Data; D009101:Multiple Myeloma / Q000235:genetics / Q000276:immunology* / Q000628:therapy; D020641:Polymorphism, Single Nucleotide / Q000276:immunology*; D013939:Thymidine Phosphorylase / Q000235:genetics* / Q000276:immunology; D014184:Transplantation, Homologous
D013939:Thymidine Phosphorylase