Understanding the mechanism of cure in testicular cancer

Pearce, Hayden (2014). Understanding the mechanism of cure in testicular cancer. University of Birmingham. Ph.D.

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The expression of cancer testis antigens (CTAgs) is normally restricted to spermatogenic cells of the testis but is also present in many cancers including testicular germ cell tumours (TGCTs). CTAg-specific T cell responses have been identified in patients with other solid tumours, and here we identified CTAg-specific T cells in TGCT patients. MAGEA-family specific T cell responses were detected in 21/49 patients with a magnitude of up to 0.149% of total peripheral blood mononuclear cells. Responses to multiple MAGEA antigens were frequently detected in seminoma patients irrespective of tumour stage. Conversely, NSGCTT patients only developed responses towards MAGEA3, which were strongly associated with disease progression. Longitudinal analysis revealed that the magnitude of MAGE-specific immune responses diminished over time by up to 95%, which correlated with the removal of tumour antigens. MAGE-specific CD8 T cells demonstrated cytotoxic potential against endogenously presented antigen.
Tumour infiltrating T cells were antigen experienced, recently activated, oligoclonal populations; many of which expressed the inhibitory molecules, TIM-3 and PD-1. Proliferation and cytokine secretion was suppressed in vivo but was rescued with in vitro stimulation, indicative of an exhausted T cell phenotype.
Our findings have significant implications in the development of novel CTAg-specific immunotherapy in patients with cancer.

Type of Work: Thesis (Doctorates > Ph.D.)
Award Type: Doctorates > Ph.D.
College/Faculty: Colleges (2008 onwards) > College of Medical & Dental Sciences
School or Department: Institute of Cancer Studies
Funders: Medical Research Council
Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
URI: http://etheses.bham.ac.uk/id/eprint/5106


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