Regulation and function of innate-like T cells

Thesis

KLRB1, encoding for CD161, is one of the most favourable prognostic pan-cancer genes. It is expressed by NK- and T-cell subsets, particularly by innate-like T cells such as MAIT and γδT cells. CD161-expressing T-cell subsets share a transcriptional and functional phenotype, including the ability to be activated by cytokines in a T-cell receptor-independent manner, similar to NK cells. The regulation and function of CD161-expressing cells as well as their role in cancer is not fully understood, however. In this study, an imaging-based high-content cytometry method, called ChipCytometry, was developed as a truly viable technique to identify and deeply phenotype CD161-positive cell types in blood and tissue. Novel mechanisms for the activation of CD161-expressing T cells were discovered by stimulation with the relatively underexplored cytokine IL-32. The ability of CD161-expressing T cells to also express IL-32 upon activation was demonstrated in vitro. To elucidate the role of IL-32 in disease, a pan-cancer IL32 gene signature was generated from The Cancer Genome Atlas (TCGA) RNA-seq data. The IL32 signature genes were associated with immune response- and T-cell activation-related pathways. Single-cell RNA-seq data from breast cancer-derived immune cells showed that IL32 gene expression and the expression of the most significant IL32 signature genes were strongly associated with innate-like T cells, including MAIT and γδT cells, in addition to memory T cells and Tregs. Finally, estimated immune cell fractions within TCGA data revealed that the favourable prognostic association of CD161 across cancers was attributable to multiple CD161-expressing cell types. These include NK cells, γδT cells, tissue-resident memory T cells, cytotoxic T cells and the still poorly studied T follicular helper cells in cancer. In summary, the findings of this study expand the knowledge of the regulation and function of CD161-expressing immune subsets and their role in cancer, setting the stage for their use as a clinical biomarker or in cancer immunotherapy.

Authors: Hagel, JP

• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English