Exploring the reciprocal relationship between the immune system and the tumour microenvironment

Pires, Ana 2020. Exploring the reciprocal relationship between the immune system and the tumour microenvironment. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

The nature of the tumour microenvironment (TME) is thought to influence the ability of tumour-specific T cells, induced naturally or by immunotherapy, to control tumour growth. This study tested the hypothesis that the composition of the TME prior to immunotherapy influences treatment success. To address this, the carcinogen 3- methylcholantrene was used to induce fibrosarcomas in Foxp3DTR mice, where Foxp3+ cells can be depleted by administering diphtheria toxin. Depletion of Foxp3+ regulatory T cells (Tregs) broadly resulted in two groups; responders, characterised by large numbers of tumour infiltrating lymphocytes (TILs) and control of tumour growth and nonresponders, characterised by fewer TILs and a reduced capacity to control tumour growth. To further identify features distinguishing responders and non-responders, an unbiased comparison of the transcriptomes of responders and non-responders revealed an inverse relationship between extracellular matrix (ECM) and T cell infiltrate. Responding tumours were T cell rich and ECM poor, whilst the inverse was observed in non-responders. Further experiments revealed that the ECM does not prevent induction of a successful response, but that loss of ECM is a consequence of an effective response. This may be due to transcriptional changes in tumour cells as a result of immune-driven tumour cell senescence. Other changes to the TME comprised development of an organised lymphatic network in responder but not non-responder tumours and tumour cell intrinsic changes. Non-responder tumour cells exhibited a stem cell-like gene expression profile and superior sphere-formation capacity, while such features were significantly reduced in responder tumours. Metastatic capacity of non-responder tumours was also suggested by the presence of fibroblast-like cells in draining and non-draining lymph nodes in all non-responder mice. These findings define an extended role for an effective immune response in widescale remodelling of the TME to favour loss of ECM, elimination of cancer stem cells and propagation of adaptive immunity.

Item Type:	Thesis (PhD)
Status:	Unpublished
Schools:	Medicine
Date of First Compliant Deposit:	11 September 2020
Last Modified:	11 Sep 2021 01:30
URI:	https://orca.cardiff.ac.uk/id/eprint/134786

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