Melanoma progression occurs despite evidence of melanoma-specific T cell activation. Chronic or repeated antigen stimulation can cause dysregulated T cell differentiation through upregulation of inhibitory receptors (immune exhaustion) or end-stage differentiation (immune senescence). This thesis therefore investigated the hypothesis that blood and skin derived T cells of melanoma patients are driven towards immune exhaustion and senescence. An increase in senescent CD8+ TEMRA cells was detected in the blood of old melanoma patients. These cells had high cytotoxic but low proliferative potential. Whilst it could not be determined whether they were melanoma specific, the TEMRA expansions occurred independently from persistent viral infections such as CMV, and their function could be boosted through p38 signalling blockade. Skin resident T cells of melanoma patients showed no increase in T cell differentiation but instead upregulation of exhaustion markers PD-1 and CTLA-4. Granzyme B and perforin, essential for granule mediated cell killing, remained low in these cells, suggesting insufficient cytotoxic function. Skin derived T cells from healthy individuals also expressed high levels of PD-1 and low levels of cytotoxic granule components. Exposure to IL-2, IL-15 and CD3/CD28 boosted perforin and granzyme expression in healthy skin cells. Conversely, PD-1 signalling blockade during CD3 stimulation increased granzyme B expression. In summary, melanoma associated immune dysfunctions were of a different nature in blood and skin T cells. Immunotherapies designed to boost immune function in patients might therefore have different efficacies in both organs.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:668430 |
| Date | January 2015 |
| Creators | Seidel, J. A. |
| Publisher | University College London (University of London) |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://discovery.ucl.ac.uk/1468230/ |
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