Molecular mechanisms of T cell homing in Hodgkin's lymphoma : implications for T-cell-based therapies

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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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.
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


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