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.

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