Vila De Mucha, Maria Antonieta;
(2021)
Transcriptional regulation of tumour infiltrating cytotoxic CD4+ T cell differentiation.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
CD4+ T cells are a crucial component of the adaptive immune response and exhibit helper or regulatory potential towards other immune cells. CD4+ T cells can also display potent cytotoxic activity in response to infection or malignancy. Tumour-infiltrating cytotoxic CD4+ T cells produce Granzyme B and kill tumour cells in an MHC class II restricted manner, so promoting the rejection of established tumours. Despite being described in several cancers, little is known about the signals that promote the differentiation of cytotoxic CD4+ T cells in tumours. In this thesis, the murine MCA205 sarcoma model was used to investigate the mechanisms by which tumour-infiltrating CD4+ T cells acquire cytotoxic activity following treatment with aCTLA-4 immunotherapy. Acquisition of a cytotoxic phenotype was largely independent of changes to chromatin accessibility in tumour-infiltrating CD4+ T cells in this model. Furthermore, aCTLA-4 treatment had limited impact on the transcriptome of effector CD4+ T cells and acted primarily by depleting regulatory T cells from the tumour microenvironment, preferentially targeting cells with high suppressive capacity. Differentiation of cytotoxic CD4+ T cells in MCA205 tumours was independent of the transcription factor T-bet, which promoted helper responses, but instead required the transcriptional repressor Blimp-1. Furthermore, both helper and cytotoxic activities of tumour-infiltrating CD4+ T cells were inhibited by the transcription factor Bcl6. Interestingly, although lacking Granzyme B (GzmB) protein, tumour-infiltrating CD4+ T cells from untreated tumours contained the same amount Gzmb mRNA as GzmB-positive cells from treated tumours. Thus, this work shows that acquisition of a cytotoxic phenotype in tumour-infiltrating CD4+ T cells is regulated at the transcriptional level by Blimp-1 and Bcl6 and may also be subject to post-transcriptional regulation.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Transcriptional regulation of tumour infiltrating cytotoxic CD4+ T cell differentiation |
| Event: | UCL (University College London) |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2021. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Cancer Bio |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10131384 |
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