Evaluating the role of CD200 signalling in renal cell carcinoma immune evasion

Rees, Elise 2020. Evaluating the role of CD200 signalling in renal cell carcinoma immune evasion. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

CD200 is a transmembrane protein with known immunosuppressive properties. This ligand functions by engaging its receptor, CD200R, found on many immune cell populations. Overexpression of CD200 has been linked to a number of cancer types as a mechanism of immune evasion. An in-human study has demonstrated a clinical benefit of targeting this ligand, which has led to the interest in identifying other cancer types that may also benefit from CD200 checkpoint inhibition. The main aim of this project was to determine whether CD200 expression was a relevant therapeutic target in renal cell carcinoma (RCC). We demonstrated that CD200 is expressed at protein level across RCC subtypes, which we suggest originates from the cell of origin for this cancer type, the renal tubules. We characterised the impact of CD200 expression level on the immune infiltrate and demonstrated a significant reduction in the presence of helper T cells, whilst NK cell presence remained relatively unaffected and suggestive of NK cell dysfunction. Using cell culture assays, we demonstrate that tumour CD200 expression inhibited CD200R+ NK cell function, both the cytotoxic and effector activity, which led to a diminished ability to kill CD200 expressing target cells. Blocking the CD200 signal was sufficient to restore NK cell activity in vitro and restore tumour cell killing. In addition to providing an inhibitory signal to interacting NK cells, the engagement of CD200R by its ligand induced the up-regulation of the Fas death receptor pathway, which resulted in apoptosis of the NK cell via induction of the caspase 8-dependent extrinsic pathway. These findings reveal a novel immunosuppressive mechanism by which both NK cell activity and presence at the tumour bed is inhibited. This study provides evidence that suggests that some RCC patients may benefit from CD200 immune checkpoint inhibition.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Biosciences
Subjects:	Q Science > Q Science (General)
Date of First Compliant Deposit:	25 January 2021
Last Modified:	26 Oct 2021 01:39
URI:	https://orca.cardiff.ac.uk/id/eprint/137928

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