Evaluating the role of CD200 in non-small cell lung carcinoma immune evasion

Lovatt, Charlotte 2022. Evaluating the role of CD200 in non-small cell lung carcinoma immune evasion. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Lung cancer is the 3rd most common cancer in the UK, accounting for 13% of all new cancer cases and is the most common cause of cancer death in the UK, accounting for 21% of all cancer deaths. Over recent years, the introduction of immunotherapies targeting the PD-1/PDL1 immune checkpoint pathway has revolutionised the treatment of non-small cell lung carcinoma (NSCLC) patients; as a tumour with a typically highly infiltrated immune reactive tumour microenvironment (TME) rich in neoantigens, NSCLC tumours represent an ideal candidate for immunotherapies, as reflected in the durable clinical efficacy seen in some responder patients. However, most patients treated with PD-1/PD-L1 immunotherapies either demonstrate an initial response followed by disease progression or, in the case of 47-63% of patients, demonstrate no response or benefit. Therefore, identification of predictive markers of immune checkpoint inhibitor (ICI) therapy response or the generation of multi-modality immunological therapies targeting multiple immune checkpoints could greatly improve the success of PD-1/PD-L1 ICI therapies in NSCLC. One of the most promising strategies for overcoming resistance and prolonging therapeutic benefit from ICIs is the use of dual immune checkpoint blockade. Therefore, the aim of this thesis was to determine whether the immune checkpoint CD200 may be a relevant immunotherapeutic target in NSCLC patients. CD200 is a type I transmembrane glycoprotein structurally related to the B7 family of receptors that signals through its receptor, CD200R, which is expressed on several immune cell populations including those of myeloid lineage, B cells, NK cells and activated T cells. Engagement of CD200R results in a negative immunoregulatory signal to maintain immune homeostasis and prevent over-activation of the immune system. CD200 is also expressed by several solid and haematological malignancies, with its expression correlating with an increase in immunosuppressive Treg cells, a decrease in memory T cells, and dysfunction of cytotoxic effector NK cells. Furthermore, CD200 is a potent regulator and suppressor of myeloid cell function, suggesting that targeting CD200 signalling may decrease immune suppression and increase the anti-tumour immune response. As a critical regulator of immune homeostasis in normal lung, CD200 may also be expressed by tumour cells to evade immune attack and promote tumour growth. In this thesis, CD200 expression was first characterised in the normal mouse and human lung where it was demonstrated to be strongly expressed throughout the distal lung by both type I and type II alveolar cells. Upon malignant transformation, CD200 expression was demonstrated on both SCC and adenocarcinoma tumours, although to a greater extent in adenocarcinoma tumours. We suggest that type II alveolar cells, the predominant cell of origin v of adenocarcinoma tumours and some SCC tumours, retain CD200 expression upon transformation as a method of immune evasion. Furthermore, using a combined RNA-seq and IHC labelling technique the relationship between tumour CD200 expression and the absolute and relative frequencies of infiltrating immune cells was established. In SCC and adenocarcinoma tumours, CD200 expression positively correlated with the frequencies of immunosuppressive Tregs and in adenocarcinoma tumours, tumour CD200 expression consistently negatively correlated with the frequencies of cytotoxic NK cells. In vitro analysis of CD200R+ NK cell activity demonstrated that CD200+ tumour cells induce NK cell dysfunction as characterised by decreased degranulation, inhibited cytokine production, altered activating receptor expression and a decreased capacity to kill tumour cells. Blocking of CD200 with an antibody was sufficient to restore the NK cell anti-tumour response and increase tumour cell death, suggesting that blocking CD200 signalling in CD200+ tumours could increase NK cellmediated tumour cell killing. Furthermore, single-cell analysis and IHC labelling demonstrated that CD200R is expressed on almost all of the infiltrating immune cell subtypes studied, suggesting immunoregulatory control of the immune response beyond that which was studied in this thesis. Taken together, this data suggests a mechanism by which NSCLC tumour cells express CD200 as a mechanism of immune evasion and that blocking CD200 signalling alone, or in combination with PD-1 inhibition to synergistically increase immune checkpoint therapy efficacy, may represent a novel therapeutic target in NSCLC.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Biosciences
Subjects:	Q Science > Q Science (General)
Date of First Compliant Deposit:	26 January 2023
Date of Acceptance:	20 January 2023
Last Modified:	03 Feb 2023 11:17
URI:	https://orca.cardiff.ac.uk/id/eprint/156282

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