The human T-box mesodermal transcription factor Brachyury is a candidate target for T-cell-mediated cancer immunotherapy.
OBJECTIVE
Identification of tumor antigens is essential in advancing immune-based therapeutic interventions in cancer. Particularly attractive targets are those molecules that are selectively expressed by malignant cells and that are also essential for tumor progression.


RESULTS
We have used a computer-based differential display analysis tool for mining of expressed sequence tag clusters in the human Unigene database and identified Brachyury as a novel tumor antigen. Brachyury, a member of the T-box transcription factor family, is a key player in mesoderm specification during embryonic development. Moreover, transcription factors that control mesoderm have been implicated in the epithelial-mesenchymal transition (EMT), which has been postulated to be a key step during tumor progression to metastasis. Reverse transcription-PCR analysis validated the in silico predictions and showed Brachyury expression in tumors of the small intestine, stomach, kidney, bladder, uterus, ovary, and testis, as well as in cell lines derived from lung, colon, and prostate carcinomas, but not in the vast majority of the normal tissues tested. An HLA-A0201 epitope of human Brachyury was identified that was able to expand T lymphocytes from blood of cancer patients and normal donors with the ability to lyse Brachyury-expressing tumor cells.


CONCLUSIONS
To our knowledge, this is the first demonstration that (a) a T-box transcription factor and (b) a molecule implicated in mesodermal development, i.e., EMT, can be a potential target for human T-cell-mediated cancer immunotherapy.
Palena
Claudia
C
Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA.
Polev
Dmitry E
DE
Tsang
Kwong Y
KY
Fernando
Romaine I
RI
Litzinger
Mary
M
Krukovskaya
Larisa L
LL
Baranova
Ancha V
AV
Kozlov
Andrei P
AP
Schlom
Jeffrey
J
D002277:Carcinoma; D045744:Cell Line, Tumor; D017931:DNA Primers; D018076:DNA, Complementary; D004847:Epithelial Cells / Q000502:physiology; D020224:Expressed Sequence Tags; D005326:Fetal Proteins / Q000235:genetics* / Q000276:immunology*; D015789:HLA-A2 Antigen / Q000378:metabolism; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D008648:Mesoderm / Q000502:physiology; D010446:Peptide Fragments / Q000737:chemistry; D012334:RNA, Neoplasm / Q000235:genetics / Q000302:isolation & purification; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020825:T-Box Domain Proteins / Q000235:genetics* / Q000276:immunology*; D000098908:Brachyury Protein
D017931:DNA Primers; D018076:DNA, Complementary; D005326:Fetal Proteins; D015789:HLA-A2 Antigen; D010446:Peptide Fragments; D012334:RNA, Neoplasm; D020825:T-Box Domain Proteins; D000098908:Brachyury Protein