Abstract
Extracellular vesicles have been recently shown to add a new dimension to cell-to-cell communication. This has high relevance for cancers as tumour-derived extracellular vesicles have been shown to contribute to immune suppression, angiogenesis and metastasis in solid cancers. However, the role of lymphoma-derived extracellular vesicles has been investigated to a far lesser extent. Diffuse Large B-Cell Lymphoma (DLBCL) is the most common forms of non-Hodgkin lymphoma yet novel treatment options are significantly limited. The tumour microenvironment (TME) may be one target for novel treatment options, however, the role of the TME in DLBCL is not yet fully understood.Fibroblast Reticular Cells (FRCs), immunologically specialized myofibroblasts of the lymphoid tissue, have been shown to play an important role in the immune response as they provide strength and flexibility to the lymph node, produce the extracellular matrix and are constantly communicating with T lymphocytes and dendritic cells. FRCs thus play a key role in the immune response. As one of the major components of the TME, FRCs could also have an important role in DLBCL pathogenesis an in tumour-mediated immunosuppression.
This research explores the role of DLBCL small extracellular vesicles in the creation of a TME that is conducive to the growth, proliferation and metastasis of tumour cells, with a particular focus on stromal cells. Our results showed that FRCs actively uptake DLBCL derived small extracellular vesicles, potentially transferring proteins and nucleic acid material to the FRCs. As a result of lymphoma extracellular vesicles uptake, FRCs developed an inflammatory-cancer associated fibroblast (CAFs)-like phenotype and reprogram their transcriptional profile. Further analysis revealed that stromal cell conditioned with DLBCL derived small extracellular vesicles uptake showed significant morphology changes resulting in altered ECM remodelling, T cells migration and adhesion to the tumour conditioned FRCs network. Tumour extracellular vesicles conditioned FRCs were also shown to negatively regulate the cytolytic activity of T cells against tumour cells through the defective formation of lytic synapse.
These results suggested that DLBCL-derived small extracellular vesicles promoted remodelling of the stromal network that resulted in the creation of an ideal tumour-supportive environment.
| Date of Award | 1 Apr 2020 |
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| Original language | English |
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| Supervisor | Alan Ramsay (Supervisor) & Stephen Devereux (Supervisor) |