The role of natural killer cells in non-small cell lung cancer

Abstract

Background and Aims: Natural killer (NK) cells are innate immune cells with the ability to kill tumour cells upon first encounter with them. Accumulating evidence suggests that NK cells may play an important role in anti-tumour immunity and the prevention of metastasis. Recent findings have revealed that there are several distinct populations of NK cells with diverse characteristics within peripheral tissues. Despite this however, knowledge of the functional status of NK cells in non-small cell lung cancer (NSCLC) is still lacking. The work in this thesis aimed to broadly understand the behaviour and functions of NK cells that infiltrate NSCLC tumours and whether they differ from the cells found in blood or that infiltrate lung. Here, we performed bulk and single cell transcriptomic analysis of NK cells isolated from NSCLC tumours and adjacent unaffected lung tissue from patients with treatment naïve lung cancer. To further understand the role of tumour-infiltrating NK cells in the context of the tumour microenvironment, more specifically, how their functions might differ in tumour microenvironments that are either rich or poor in terms of CD8+ T cell density we preselected tumour samples according to CD8+ T cell expression. By selecting our samples in this way, we were able to indirectly correlate the presence of tumour-infiltrating NK cell subpopulations with improved outcomes. Results: Tumour infiltrating NK cells comprised a significantly smaller fraction of the total lymphocyte population in NSCLC compared to adjacent lung and peripheral blood (5% versus 19% and 15% respectively). Both CD56+CD16+ and CD56+CD16neg populations were identified in NSCLC at both the protein and bulk transcriptional level. Single cell RNA-seq analysis of NK cells isolated from NSCLC tumour and lung tissue identified major differences in the transcriptional programs of tumour-infiltrating NK cells. We identified 7 clusters of tumour-infiltrating NK cells with distinct gene expression programs indicative of functional specialisation, particularly in tumours with high CD8+ T cell density (TILHigh). CD16+ NK cells present in TILHigh tumours were enriched for transcripts linked to cytotoxicity, pro-inflammatory cytokines and enhanced effector function suggesting a role for direct tumour cell killing. The CD16neg NK cells however, comprised several specialist subpopulations of tumour infiltrating NK cells including a unique tissue resident population (trNK) with ‘memory-like’ features. We also identified an ILC3-like subset with transcriptional features linked to activation, immune cell recruitment and lymphoid tissue inducing properties. Conclusion: The data presented for the work of this thesis has identified unique subpopulations of NK cells that are potentially acting synergistically with ILC3 cells and CD8+ T cells to not only directly kill tumour cells but also serving to co-ordinate and initiate the adaptive immune responses to cancer in TILHigh tumours. We have identified an as yet unexplored and distinct trNK cell population with ‘memory-like’ features in NSCLC tumour. Their presence in TILHigh tumours suggests that they are co-operating with CD8+ T cells to mediate the robust anti-tumour responses seen in these patients.

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Identifiers

ORCID for Tilman Sanchez-Elsner: orcid.org/0000-0003-1915-2410

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