Investigation of cellular components of the anti-tumour adaptive immune response in humans

Abstract

The adaptive immune response to tumours plays a major role in determining outcome. Patients whose tumours contain high numbers of infiltrating lymphocytes (TIL), a marker of on-going immune attack, are likely to live longer. The improved understanding of immune cells in the tumour microenvironment has led to ground-breaking therapies (e.g. anti-CLTA4 and anti-PD1), in which targeting specific components of the anti-tumour immune response can lead to dramatically improved patient survival. The studies here focus on HNSCC (head and neck squamous cell carcinoma) and NSCLC (non-small cell lung cancer) to explore how differences in the adaptive immune response reflected in tumour infiltrating lymphocyte density, translates into differing efficacies and phenotypes of the different lymphocyte populations. Monitoring of immunotherapy clinical trials and evaluation of changes relies on a stable signal over time. To address this, multiple tumour replicates were investigated between diagnostics biopsy and surgical resection in HNSCC. An immunologically focused transcriptomic and CD8 histology evaluation showed that tumours are stable, both over time and space. In HNSCC, HPV(+) and (-) disease display a significantly different patient survival, even among the TIL high group. Transcriptomic and histological assessment of these tumours at the bulk tissue level, revealed that this difference was driven by quantitative rather than qualitative differences in the T cells. However, a differential B cell signature emerged between HPV(+) and (-) tumours. Isolation of specific immune cell subsets (CD8+ T cells and B cells) from NSCLC and HNSCC enabled higher resolution analysis of immune cells in different disease settings (TIL density). Tissue resident memory T cells (TRM) were enriched in tumours, the effector function of the TRM cells were also found to be superior in TILHi tumours. The TRM cells were also prognostic, where higher numbers in the tumour conferred a survival benefit in NSCLC, and a trend towards improved survival in HNSCC. B cells from CD8Hi and CD8Lo NSCLC were assessed using single cell transcriptomics, and have been shown to exhibit different cellular characteristics depending on T cell density. B cells in immune-rich tumours (CD8Hi) show a response to cytokine stimulus, the ability to present antigens and evidence of a germinal centre reaction. The B cells in CD8Lo tumours exhibit an alternative activation profile with increased markers of cellular stress and reduced interactions with co-stimulatory cells. The findings show that many of the cellular components of the immune infiltrate show significant qualitative differences which appear to associate with the density of CD8+ T cells. Future work needs to explore the control processes and cross-talk between the cells of the adaptive immune system that may be involved in determining these differences.

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