<p><strong>INTRODUCTION: </strong>Pre-clinical and clinical data strongly support the feasibility of employing immunotherapy as a strategy to treat cancer.</p> <p><strong>METHODS: </strong>Using the B16F10 murine melanoma model, we have been investigating mechanisms of T cell-mediated antitumor immunity following immunization with dopachrome tautomerase (DCT), a melanoma-associated antigen.</p> <p><strong>RESULTS: </strong>In <strong>Chapter 2</strong>, we uncovered an interesting dichotomy whereby DCT-specific CD4<sup>+</sup> T cell-mediated tumor protection and autoimmunity are dependent on IL-4/STAT-6 and IFN-g/STAT-4, respectively. Our data also revealed that this phenomenon is extrinsic of CD4<sup>+</sup> T cell polarization.</p> <p>To gain further insight into the targets recognized by CD4<sup>+</sup> T cells, we conducted in <strong>Chapter 3</strong> extensive CD4<sup>+</sup> T cell epitope mapping experiments using overlapping peptide libraries. Interestingly, while we were able to identify “helper” epitopes within DCT that were required for maximal CD8<sup>+</sup> T cell expansion, we were unable to identify “effector” epitopes responsible for tumor rejection. Further examination of the requirements for the generation of CD4<sup>+</sup> T cell effector epitopes showed that post-translational modifications of the protein were involved.</p> <p>In <strong>Chapter 4</strong>, we investigated the modest efficacy afforded by DCT immunization in the context of established B16F10 melanomas. Using intratumoral transcriptional analysis, we demonstrated that the vaccine rapidly promoted an IFN-g-dependent immunosuppressive state inside the tumor. Concurrent treatment with the immunomodulatory antibodies anti-4-1BB and anti-PD-1 effectively counteracted this tumor immunosuppression, resulting in complete regression of tumors and long-term survival in 70% of the mice.</p> <p><strong>CONCLUSIONS: </strong>The research described in this thesis sheds new light into the mechanisms by which vaccine-mediated CD4<sup>+</sup> T cell responses participate to tumor rejection and autoimmunity. Moreover, our findings indicate that cancer vaccine-induced tumor immunosuppression significantly limits tumor regression, emphasizing the requirement of combinatorial approaches for successful cancer immunotherapy. Overall, our research offers new insight for future vaccine development.</p> / Doctor of Philosophy (Medical Science)
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/11156 |
| Date | 10 1900 |
| Creators | Bernard, Dannie |
| Contributors | Wan, Yonghong, Bramson, Jonathan, Ashkar, Aliahmad |
| Source Sets | McMaster University |
| Detected Language | English |
| Type | thesis |
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