Tissue resident CD8 T cells subsets: prognostic significance in colorectal cancer

Talhouni, Shahd (2022) Tissue resident CD8 T cells subsets: prognostic significance in colorectal cancer. PhD thesis, University of Nottingham.

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Abstract

The past few years have seen remarkable success in the field of oncology with the advent of cancer immunotherapies and checkpoint inhibitors. The effectiveness of immunomodulatory strategies has been shown to depend on natural intra-tumoral T cell infiltration and on reactivation of pre-existing immunity via inhibition of inhibitory checkpoints on T cells. T-cell membrane microdomains are enriched with proteins and glycolipids collectively involved in cell activation and signal transduction. Tetraspanin-enriched microdomains are an example of such microdomains that have been shown to play a pivotal role in T-cell regulation. One such tetraspanin protein is TSPAN32 that has not been widely studied. For the purpose of further studying the immuno-regulatory role of TSPAN32, especially in its ability to inhibit T cell proliferation, we developed an innovative immunisation method using plasma membrane glycolipid extraction of TSPAN32 transfected cells to produce an anti-TSPAN32 antibody. Developing a fully function TSPAN32 monoclonal antibody could help further understand its immune function and could also potentially help in the development of novel immunotherapies that improve immune response in cancers.

Among different tumour infiltrating T cells, high levels of CD8 T cell infiltration – a hallmark of immunologically “hot” tumours - are a favourable indicator for patient survival and immunotherapy responsiveness. In colorectal cancer (CRC), the Immunoscore index developed based on the density of CD3+ and CD8+ TILs infiltrating the centre and invasive margin of the tumour, was found to be a better predictor of patient survival than the current histopathological methods. . In our study, we aimed to investigate the predictive role of intraepithelial and stromal CD3+ and CD8+ T cells in three different regions of the tumour luminal side (LS), the centre of the tumour (CT), the invasive margin (IM) and the adjacent normal tissue in CRCs. The results showed high infiltration of CD3+ and CD8+ T cells in tumour regions (LS, CT and IM), but not in the adjacent normal tissue was significantly associated with better survival in patients with CRC.

CRC patients are classified based on the occurrence of left or right colon tumours which have been shown to have different phenotypic characteristics and tumour micro-environment (TME). To define the differences in the immune infiltrates between RCRCs and LCRCs, we compared the distribution of CD8+ TILs and tissue-resident T cells (CD103+ TILs) between RCRCs and LCRCs. We found that RCRCs were associated with significantly higher infiltration of intraepithelial CD8 TILs and CD103 TILs compared to LCRCs. Furthermore, we have shown that high infiltration of intraepithelial CD103 TILs was an independent predictor of patient survival in RCRCs.

Tumour infiltrating CD8 T cells represent a heterogeneous cell population comprising tumour-specific T cells and bystander T cells. In solid tumours, co-expression of CD39 and CD103 on CD8 T cells has been shown to identify tumour reactive tissue resident memory T cells (TRM). Our study presents the largest study (n=1000) yet to compare the landscape and prognostic significance of recently activated tumour specific TRM cells and other CD8+ TILs phenotypes within the TME of colorectal tumours. Using multiplex immunohistochemistry staining, followed by training using advanced image-analysis software, CD8+ TILs, co-expressing CD103 and/or CD39 on their surface, were detected and quantified within tumour epithelium and stroma of each TMA core. CD8 TRM T-cells were shown to be an independent predictor of survival in CRC. We further investigated the prognostic role of this unique population between different CRC tumour sidedness and showed that in LCRCs, the only CD8 phenotype that predicted survival was the recently activated TRM CD8-T cells. In contrast, RCRCs with heavily infiltrated tumours regardless of the presence of this TRM subset still had good survival.

Item Type: Thesis (University of Nottingham only) (PhD)
Supervisors: Ramage, Judith
Spendlove, Ian
Keywords: T cells, Colorectal cancer, Tissue resident T cells, TSPAN32
Subjects: W Medicine and related subjects (NLM Classification) > WI Digestive system
Faculties/Schools: UK Campuses > Faculty of Medicine and Health Sciences > School of Medicine
Item ID: 68269
Depositing User: Talhouni, Shahd
Date Deposited: 01 Aug 2022 04:40
Last Modified: 01 Aug 2022 04:40
URI: http://eprints.nottingham.ac.uk/id/eprint/68269

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