Wakatsuki, Ayako; (2002) Towards the design of tumour vaccines: Induction of immune responses to self antigens. Doctoral thesis (Ph.D.), University College London.

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Abstract

Despite the increasing incidence of cancer worldwide, tumour immunotherapy available in clinics to date is very limited with variable results. As the number of cancer patients is expected to continue to rise, there is an increasing demand for good vaccines. Evidence suggests that tumour cells arising spontaneously present self molecule-derived antigens. Due to the process of thymic selection, our immune system has been designed for self recognition but not self activation. This is achieved by T cell receptors bearing different affinities to different antigens. Briefly, T cells in the periphery can only respond to "high-affinity" antigens, and are incapable of eliciting a response to self antigens, or "low-affinity" antigens. Thus, in order to elicit an effective antitumour response we need to understand how our immune system responds to "low-affinity" self antigens. To investigate the mechanisms of low-affinity recognition by T cells, the ability of differentially matured bone marrow-derived dendritic cells (DCs) to induce low- affinity T cell responses was assessed. In the syngeneic mixed lymphocyte reaction, pathogen-derived products (LPS, cholera toxin and pertussis toxin), but not cAMP inducers (dbcAMP, forskolin and PGE2) drive maturation and differentiation of DCs and subsequent Th1 responses. Pertussis toxin-treated DCs were found to be potent stimulators of naive syngeneic CD4+ and CD8+ T cells, and they do so independently of the signalling through MHC-TcR interaction or B7-mediated costimulation. In the F5 transgenic system, "low-affinity" antigen presented on mature DCs induced proliferation and IFNγ production of naive T cells, but not cytotoxic function. Remarkably, cytotoxicity of low-affinity targets was improved by priming T cells with "high-affinity" antigen. Thus, data suggest that there are limitations to the ability of DCs to induce low-affinity T cell responses, and that manipulation of antigens recognised by the T cells may be the key to inducing effective antitumour immune responses.

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