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.

Download full-text


Available from: Romaine I Fernando, May 09, 2014
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Therapeutic cancer vaccines have the potential of being integrated in the therapy of numerous cancer types and stages. The wide spectrum of vaccine platforms and vaccine targets is reviewed along with the potential for development of vaccines to target cancer cell "stemness," the epithelial-to-mesenchymal transition (EMT) phenotype, and drug-resistant populations. Preclinical and recent clinical studies are now revealing how vaccines can optimally be used with other immune-based therapies such as checkpoint inhibitors, and so-called nonimmune-based therapeutics, radiation, hormonal therapy, and certain small molecule targeted therapies; it is now being revealed that many of these traditional therapies can lyse tumor cells in a manner as to further potentiate the host immune response, alter the phenotype of nonlysed tumor cells to render them more susceptible to T-cell lysis, and/or shift the balance of effector:regulatory cells in a manner to enhance vaccine efficacy. The importance of the tumor microenvironment, the appropriate patient population, and clinical trial endpoints is also discussed in the context of optimizing patient benefit from vaccine-mediated therapy.
    Full-text · Article · Jun 2014 · Advances in Cancer Research
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The respiratory mucosa is a major coordinator of the inflammatory response in chronic airway diseases, including asthma and chronic obstructive pulmonary disease (COPD). Signals produced by the chronic inflammatory process induce epithelial mesenchymal transition (EMT) that dramatically alters the epithelial cell phenotype. The effects of EMT on epigenetic reprogramming and the activation of transcriptional networks are known, its effects on the innate inflammatory response are underexplored. We used a multiplex gene expression profiling platform to investigate the perturbations of the innate pathways induced by TGF β in a primary airway epithelial cell model of EMT. EMT had dramatic effects on the induction of the innate pathway and the coupling interval of the canonical and noncanonical NF- κ B pathways. Simulation experiments demonstrate that rapid, coordinated cap-independent translation of TRAF-1 and NF- κ B2 is required to reduce the noncanonical pathway coupling interval. Experiments using amantadine confirmed the prediction that TRAF-1 and NF- κ B2/p100 production is mediated by an IRES-dependent mechanism. These data indicate that the epigenetic changes produced by EMT induce dynamic state changes of the innate signaling pathway. Further applications of systems approaches will provide understanding of this complex phenotype through deterministic modeling and multidimensional (genomic and proteomic) profiling.
    Full-text · Article · Oct 2013
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Cancer vaccine development is in the process of becoming reality in future, due to successful phase II/III clinical trials. However, there are still problems due to the specificity of tumor antigens and weakness of tumor associated antigens in eliciting an effective immune response. Computational models to assess the vaccine efficacy have helped to improve and understand what is necessary for personalized treatment. Further research is needed to elucidate the mechanisms of activation of antigen specific cytotoxic T lymphocytes, decreased TREG number functionality and antigen cascade, so that overall improvement in vaccine efficacy and disease free survival can be attained. T cell epitomic based in sillico approaches might be very effective for the design and development of novel cancer vaccines.
    Preview · Article · Jul 2013 · Asian Pacific journal of cancer prevention: APJCP
Show more