Investigation into the heterogeneity of tissue resident T cell populations in human solid tumours

Abstract

The role of the immune system in the control of malignancies is now well established. The presence of cytotoxic T cells (CTLs) has been shown to be prognostic in a wide range of malignancies. The extent of the heterogeneity of the anti-tumour between discrete locations in a single patient’s tumour and across multiple patient’s is currently unknown. Therefore, this thesis aimed to investigate the biological variability in immune signatures, both within and between patients.

In the first section of this thesis I investigated the intra-patient variability in the anti-tumour immune response, over time and at different locations within the tumour, in Head and Neck Squamous Cell Carcinoma (HNSCC) (Chapter 3). This data suggested that at a global level the immunological signature of each patient was similar, although from preliminary single cell analysis there appeared to be significantly heterogeneity masked in the bulk signature. Concurrently, our group had generated a transcriptome profiling of CD8+ T cells isolated from human Lung Tumours, which suggested a significant proportion were tissue resident (CD103+) CD8+ cells. Therefore, the next stage was to complete flow cytometry investigations into the protein expression of these cells (Chapter 4). This analysis suggested that CD103+ CD8+ cells represented a population of tissue resident T cellsin human solid tumours, RNA-seq of purified populations (Chapter 5) and single cell RNA-seq (Chapter 6) was completed to understand this population in more detail. This further transcriptomic profiling highlighted a unique population of tumour specific TRM that appeared to be highly proliferative and expressed superior functional properties (cytokines, chemokines and cytotoxic molecules).

In conclusion, we have begun to clarify the signature of these prognostic tissue resident cells in human anti-tumoural immunity at the bulk and single cell level, highlighting a unique subpopulation. Future work will aim to complete functional investigates and additional genomewide methodologies to study these population in-vivo.

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Identifiers

ORCID for Pandurangan Vijayanand: orcid.org/0000-0001-7067-9723

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