Investigating the role of Th17 cells in colorectal cancer

Thesis

In the two decades since their discovery, T helper type 17 (Th17) cells have become widely accepted as key immune sentinels at mucosal barriers such as the gut. During homeostasis, they play an important role in protecting against microbial translocation by strengthening the epithelial cell layer present within these niches and by enhancing the production of antimicrobial peptides. These environments can be highly dynamic and Th17 cells have evolved to display functional plasticity, rapidly upregulating a number of inflammatory programmes in response to physiological or immunological stimuli.

However, aberrant activation of these inflammatory programmes has the capacity to drive a number of pathological processes, including the initiation and development of colorectal cancer (CRC). Despite an abundance of literature suggesting that Th17 cells are deleterious in CRC, accumulating evidence has implied that some Th17 populations may serve a more protective role. One reason for these seemingly antithetical functions may be due to the transcriptional heterogeneity which Th17 cells display.

In this thesis, we first explore the extent of this heterogeneity in human CRC using a variety of computational techniques before validating our findings ex vivo using patient resections. We describe a population of CD69+ CD103+ Th17 cells that are enriched in the tumours of some patients. We speculate that this population, which we term Th17 resident memory (Th17RM) cells due to their enrichment with several tissue resident memory T cell markers, develop from a pool of homeostatic Th17 cells in the presence of inflammatory cytokines such as IFN-g, TNF-a, TGF-b1 and IL-18 derived from tumour associated macrophages. Th17RM cells are clonally expanded and exhibit gene programmes that suggest they proliferate in response to antigen within the tumour microenvironment. Tumours that are enriched with Th17RM-associated genes correlate with improved prognosis in patients with colon adenocarcinoma and this protection is similarly observed in those with melanoma. However, such protection is not afforded to patients with rectal adenocarcinoma, lung or breast carcinomas. Th17RM cells are enriched with cytotoxic molecules such as granzyme A, granzyme B, IFN-g and TNF-a and can be found embedded within the tumour epithelium, suggesting that this protection might at least partially be mediated by direct cytotoxicity.

Authors: Pang, D

• DOI: 10.5287/ora-qz8ndkynr
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English