The Human T-Box Mesodermal Transcription Factor Brachyury Is a Candidate Target for T-Cell-Mediated Cancer Immunotherapy

George Mason University, 페어팩스, Virginia, United States
Clinical Cancer Research (Impact Factor: 8.72). 05/2007; 13(8):2471-8. DOI: 10.1158/1078-0432.CCR-06-2353
Source: PubMed


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.
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.
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.

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Available from: Romaine I Fernando, May 09, 2014
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    • "It has been shown to be selectively expressed on both primary and metastatic lesions of several carcinoma types. T-cell epitopes have been identified on the Brachyury protein that have the ability to generate human T cells capable of lysing a range of human carcinoma cells (Palena et al., 2007). This will be discussed in detail below. "
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    • "In COPD, the reticular basement membrane is fragmented with “clefts” of cells staining for MMP-9 and S100A4, hallmarks of EMT [13]. We note that airways infection with respiratory syncytial virus (RSV), the most common viral respiratory pathogen in small children which is widely considered as a risk factor for the development of allergic asthma later in life is characterized by an increased expression of SNAI1, MMP-2, and TGFβ1 [62, 63]. Finally, EMT plays a critical role in switching a primary tumor to a malignant cancer with metastatic phenotype. "
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    • "Protein or peptide had been used to stimulate immune response against the cancer employing broad range of proteins such as heat shock proteins (HSP), Agonist Peptides, Anti-idiotype antibodies (Palena et al., 2007; Bolhassini and Rafati, 2008; Ai et al., 2009). Vaccines based on proteins have stronger response on the generation of CD4+ lymphocytes, and less effective on production of Cytotoxic T lymphocytes (Ostrand Rosenberg, 2008). "
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