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Title: Molecular expression and immunotherapeutic potential of the novel tumour associated antigen T21
Author: Malhi, S. K.
Awarding Body: Nottingham Trent University
Current Institution: Nottingham Trent University
Date of Award: 2013
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The application of immunotherapeutic approaches to target tumour cells by harnessing the body’s most important defence the immune system, could provide opportunities to oppose cancer. A prerequisite of tumour immunotherapy lies in the identification of antigens that are distinctively expressed in cancer and can elicit immune responses in the tumour-bearing host. Testis clone 21 (T21) was first identified as a promising prostate-associated tumour antigen identified using modified SEREX expression cloning showing restricted protein expression to normal testis and prostate, breast, kidney, ovary, melanoma, colon and stomach cancer among others. More recently, T21 was found to share significant sequence similarity with a centrosomal protein called CEP290. This study proposed to address the current understanding of T21 through analysis of gene sequence similarities observed with CEP290 and begin to extrapolate possible functional attributes of T21 and the role it may play in cancer progression. Furthermore this investigation aimed to evaluate T21 as a prospective prognostic indicator of prostate cancer and in addition, investigate T21 as a potential target for immunotherapy. In silico sequence analysis revealed that T21 contained a 93bp region, a consequence of an alternative splicing event resulting in the retention of a CEP290 intronic region making its translation to protein unique. This finding was supported by experimental observations using PCR and northern blotting. Using this T21 “unique region” sequence, T21 mRNA and protein was shown to be expressed in some normal tissues including prostate, stomach and spinal cord when compared to testis therefore T21 cannot be considered a cancer testis antigen as previously suggested. Evidence of T21 protein expression was shown in a number of cancer tissues, however a histological study demonstrated no significant discrimination between benign and prostate cancer patients. In vitro assessment of cell proliferation following T21 gene knockdown indicated an association between T21 and increased tumour cell proliferation. Expression profiling of data obtained from Next Generation Sequencing (NGS) indicated T21 function was related to cell proliferation and survival, modulation of immune responses and suppression of regulatory processes involved in tumourigenesis. Collective evidences suggest T21 activity to be independent of that of CEP290. Finally, this study identified a novel immunogenic and naturally processed peptide target using a transgenic murine model, further verified using human cancer patient PBMCs. Future studies to determine the immunotherapeutic potential of T21 would focus on providing evidence of peptide-specific tumour killing targeting this novel antigenic sequence in the first instance.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available