Machado, Lee Richard (2005). Molecular mechanisms of T cell homing in Hodgkin's lymphoma : implications for T-cell-based therapies. University of Birmingham. Ph.D.
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Machado05PhD.pdf
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Abstract
Recent years have seen important advances in the area of T cell-based therapy for human malignancies. Epstein Barr virus-associated tumours like Hodgkin’s Lymphoma provide important models in this field. If a T cell-based therapy is to be effective however, T cells must be capable of trafficking to the tumour. To address this, the molecular mechanisms of T cell homing to Hodgkin’s Lymphoma were explored. Chemokine and adhesion receptors were examined on infiltrating T cells. CXCR3, CXCR4 and CCR7 were expressed on major T cell populations with CXCR5, CXCR6, CCR4 and CCR5 on minor populations. Tumour cells expressed CXCL10, CXCL12 and CCL21. Vessels expressed ICAM-1, CXCL12, CCL17 and CCL21. Tumour cell lines secreted factors that mediated chemotaxis of lymphoblasts in vitro and TIL demonstrated chemotaxis to CXCL12 but not CCL17. VAP-1 was expressed on vessels and a tissue-binding assay was evaluated to examine VAP-1 function. T cell clones generated as part of an existing clinical trial of adoptive T cell therapy were found to express a polarised Tc1 phenotype (CXCR3, CXCR6 and ccr5), which was typically independent of target antigen specificity, CD4/CD8 and donor status. However, lack of CCR7 expression and an inability to capture to VCAM-1 in a chemokine dependent manner suggested that clones expanded in vitro using existing protocols may be inefficient at trafficking to tumour tissue and thus may require modification of their homing phenotype.
| Type of Work: | Thesis (Doctorates > Ph.D.) |
|---|---|
| Award Type: | Doctorates > Ph.D. |
| Licence: | |
| College/Faculty: | Schools (1998 to 2008) > School of Medicine |
| School or Department: | Division of Cancer Studies |
| Funders: | None/not applicable |
| Subjects: | R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer) Q Science > QR Microbiology |
| URI: | http://etheses.bham.ac.uk/id/eprint/579 |
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