UBC Theses and Dissertations
Bioinformatics approach to investigate genetic differences underlying breast tumours with specific outcomes of adoptive T-cell therapy using a mouse model Chun, Hye-Jung
The immune system plays a critical role in cancer prevention and development. The stimulation of natural immune reaction in a cancer patient by adoptive T-cell therapy has shown success in treating metastatic melanomas and renal cell carcinomas. However, the use of adoptive T-cell therapy remains limited due to unpredictable outcomes and low response rates. In particular, adoptive T-cell therapy for breast cancer has not been realized, despite of the presence of immunogenic antigens such as over-expressed HER2, present in 20-40% of breast tumours. Using a unique transgenic mouse model, the global profiles of gene expression, miRNA abundance and single nucleotide variants (SNVs) were investigated to identify the molecular difference of murine mammary tumours with isogenic background, which exhibited complete regression (CR), partial regression (PR) or progressive disease (PD) outcome of adoptive T-cell therapy. The bioinformatics analyses were further carried out to identify uniquely activated pathways, prognostic gene expression signatures, the effect of post-transcriptional gene regulation and mutated genes unique to tumours with specific outcome. The largest differences in gene expression, miRNA and SNV profiles were repeatedly observed between the regressing (CR, PR) and non-regressing (PD) tumours, supporting the attribution of molecular differences to the immunotherapy outcome. In particular, the gene expression signatures derived from genes in immune-related pathways were experimentally validated to be strong prognostic markers for predicting the CR outcome. Comparison with the human breast cancer subtypes further revealed similarities of the non-regressing tumours with the basal subtype, and the regressing tumours with the HER2 subtype. The difference in miRNA profiles between CR and PR tumours suggested potential translational activities unique to PR, which was nearly identical to CR at the transcriptome level. The findings from this study show that tumour-derivied factors that either promote or suppress the immune system are responsible for the varying outcome of immunotherapy, and that the molecular characteristics can be further applied for the development of clinical prognostic tools, cancer vaccines and drug targets to enhance the efficacy of adoptive T-cell therapy.
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