Targeting the hypoxic tumour phenotype with T-cell immunotherapy
<p>The hypoxic tumour phenotype is a widespread phenomenon in cancers that correlates with malignant behaviour and poor clinical outcomes. The induced expression of hypoxia-regulated genes through post-translational stabilization of hypoxia-inducible factor (HIF), represent a novel class of ov...
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| Format: | Thesis |
| Language: | English |
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2004
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| _version_ | 1797096496747773952 |
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| author | Chong, T |
| author2 | Cerundolo, V |
| author_facet | Cerundolo, V Chong, T |
| author_sort | Chong, T |
| collection | OXFORD |
| description | <p>The hypoxic tumour phenotype is a widespread phenomenon in cancers that correlates with malignant behaviour and poor clinical outcomes. The induced expression of hypoxia-regulated genes through post-translational stabilization of hypoxia-inducible factor (HIF), represent a novel class of over expressed tumour antigens that may bear relevance for specific T cell immunity. To assess whether hypoxia inducible proteins can elicit specific T cell responses in vivo, experiments were carried out using complementary models. Initially, specific T cell responses to a hypoxia-regulated antigen |3 galactosidase (pgal) in a mouse melanoma model were investigated. The responses correlated to hypoxia-induced expression of (3gal in vitro, and resulted in anti-tumour effects in vivo. Next, the utility of human carbonic anhydrase 9 (CA9) as a tumour antigen was explored. In particular, renal cell carcinomas (RCC) which constitutively express CA9 as a result of HIF stabilization through loss of von-Hippel Lindau (VHL) tumour suppressor gene, were targeted. Since the HLA-A2 restricted peptide CA9254 . 2 62 was reported to be immunogenic and endogenously presented in human cells, peptide specific T cell responses were induced in vivo using HLA-A2 transgenic mice, and monitored with novel CA9-specific tetramers. Subsequently, CA9 specific T cell responses in HLA-A2 healthy donors and RCC patients were generated in vitro which recognized exogenous but not endogenously presented peptide as a result of low avidity interactions, or failure of correct processing and presentation by antigen presenting cells.</p> <p>To assess whether anti-angiogenic therapy can be combined with vaccination strategies, the combination of anti-angiogenic and specific T cell immunotherapy was explored using a novel 'metronomic dosing' regime of cytotoxic agent cyclophosphamide. A synergistic anti-tumour effect in a murine melanoma model was demonstrated, while sparing a population of memory T cells that were subsequently capable of re-expansion.</p> <p>Finally, a novel iron chelator desferri-exochelin was found to induce HIF and downstream targets, suggesting that specific T cell immunotherapy against hypoxiaregulated targets may be enhanced through chemical means. Additionally, desferriexochelin was anti-angiogenic in vitro, and inhibited tumour cell proliferation through HIF independent pathways.</p> |
| first_indexed | 2024-03-07T04:42:41Z |
| format | Thesis |
| id | oxford-uuid:d22f1d74-44eb-4560-9249-f6127accd1b1 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T04:42:41Z |
| publishDate | 2004 |
| record_format | dspace |
| spelling | oxford-uuid:d22f1d74-44eb-4560-9249-f6127accd1b12022-03-27T08:02:05ZTargeting the hypoxic tumour phenotype with T-cell immunotherapyThesishttp://purl.org/coar/resource_type/c_db06uuid:d22f1d74-44eb-4560-9249-f6127accd1b1ImmunologyImmunotherapyCancer vaccinesT cellsCancerImmunological aspectsEnglishPolonsky Theses Digitisation Project2004Chong, TCerundolo, VHarris, A<p>The hypoxic tumour phenotype is a widespread phenomenon in cancers that correlates with malignant behaviour and poor clinical outcomes. The induced expression of hypoxia-regulated genes through post-translational stabilization of hypoxia-inducible factor (HIF), represent a novel class of over expressed tumour antigens that may bear relevance for specific T cell immunity. To assess whether hypoxia inducible proteins can elicit specific T cell responses in vivo, experiments were carried out using complementary models. Initially, specific T cell responses to a hypoxia-regulated antigen |3 galactosidase (pgal) in a mouse melanoma model were investigated. The responses correlated to hypoxia-induced expression of (3gal in vitro, and resulted in anti-tumour effects in vivo. Next, the utility of human carbonic anhydrase 9 (CA9) as a tumour antigen was explored. In particular, renal cell carcinomas (RCC) which constitutively express CA9 as a result of HIF stabilization through loss of von-Hippel Lindau (VHL) tumour suppressor gene, were targeted. Since the HLA-A2 restricted peptide CA9254 . 2 62 was reported to be immunogenic and endogenously presented in human cells, peptide specific T cell responses were induced in vivo using HLA-A2 transgenic mice, and monitored with novel CA9-specific tetramers. Subsequently, CA9 specific T cell responses in HLA-A2 healthy donors and RCC patients were generated in vitro which recognized exogenous but not endogenously presented peptide as a result of low avidity interactions, or failure of correct processing and presentation by antigen presenting cells.</p> <p>To assess whether anti-angiogenic therapy can be combined with vaccination strategies, the combination of anti-angiogenic and specific T cell immunotherapy was explored using a novel 'metronomic dosing' regime of cytotoxic agent cyclophosphamide. A synergistic anti-tumour effect in a murine melanoma model was demonstrated, while sparing a population of memory T cells that were subsequently capable of re-expansion.</p> <p>Finally, a novel iron chelator desferri-exochelin was found to induce HIF and downstream targets, suggesting that specific T cell immunotherapy against hypoxiaregulated targets may be enhanced through chemical means. Additionally, desferriexochelin was anti-angiogenic in vitro, and inhibited tumour cell proliferation through HIF independent pathways.</p> |
| spellingShingle | Immunology Immunotherapy Cancer vaccines T cells Cancer Immunological aspects Chong, T Targeting the hypoxic tumour phenotype with T-cell immunotherapy |
| title | Targeting the hypoxic tumour phenotype with T-cell immunotherapy |
| title_full | Targeting the hypoxic tumour phenotype with T-cell immunotherapy |
| title_fullStr | Targeting the hypoxic tumour phenotype with T-cell immunotherapy |
| title_full_unstemmed | Targeting the hypoxic tumour phenotype with T-cell immunotherapy |
| title_short | Targeting the hypoxic tumour phenotype with T-cell immunotherapy |
| title_sort | targeting the hypoxic tumour phenotype with t cell immunotherapy |
| topic | Immunology Immunotherapy Cancer vaccines T cells Cancer Immunological aspects |
| work_keys_str_mv | AT chongt targetingthehypoxictumourphenotypewithtcellimmunotherapy |