Abstract
Natural killer (NK) cells are innate immune cells which play a key role in shaping the immune response against cancer. Initially hailed for their potential to recognise and eliminate tumour cells, their application has been greatly hindered by the immunosuppressive tumour microenvironment (TME) which suppresses NK functions (e.g., cytotoxicity). This dysfunctional state that is accompanied by phenotypic changes such as upregulation of inhibitory receptors and downregulation of activating receptors, forms the basis of what many researchers have referred to as ‘exhausted’ NK cells. However, there is no consensus on whether these phenotypes are sufficient to define an exhausted state of the NK cell. While recent advances in checkpoint inhibition appear to show promise in early-stage pre-clinical studies, much remains to be fully explored and understood in the context of the TME. The TME is where the NK cells are subjected to interaction with various cell types and soluble factors, which could exert an inhibitory effect on NK cytotoxicity. In this review, we provide an overview of the general markers of NK cell exhaustion viz, the surface activating and inhibitory receptors. We also highlight the potential role of T-box transcription factors in characterising such a dysfunctional state and discuss the often-overlooked mechanism of cell cytoskeletal dynamics in regulating NK cell function. These aspects may further contribute to NK exhaustion or NK revival in cancer and may open new avenues to explore cancer treatment strategies.
Highlights
Natural killer cells (NK) belong to the family of Group 1 Innate Lymphoid Cells (ILC), and have been well-characterised for their cytotoxic functions against a wide variety of pathogens, infections and cancers [1].Distinct from the adaptive immune cells, NK cells are purported to recognise target cells without prior antigen sensitisation [2]
Classical schools of thought imply that NK cell activation depends heavily on the functional state and balance of surface activating and inhibitory receptors [2], which recognise stress-induced ligands or detect a ‘missing self’, characterised by the lack of MHC class I molecules on cancer cells or infected cells [1]
These characteristics make NK cells an attractive immune sentinel for cancer immunomodulation, especially in view of the shortfalls in immunotherapy, which has far been largely focused on CAR-T and immune checkpoint inhibition
Summary
Natural killer cells (NK) belong to the family of Group 1 Innate Lymphoid Cells (ILC), and have been well-characterised for their cytotoxic functions against a wide variety of pathogens, infections and cancers [1]. Peripheral NK cells from cancer patients as well as tumourinfiltrating NK cells exhibit reduced effector functions such as (i) decreased expression of the membrane protein CD107a, which is a degranulation marker, (ii) decreased secretion of cytokines IFNg [9, 10] and TNFa [10], and the cytotoxic molecules, perforin [11] and granzyme [12], all of which result in reduced NK cell function against tumour cells This loss of function in NK cells is often referred to as ‘exhaustion’, a phenomenon which was first observed in effector T cells present in persistent chronic infections and cancers [13, 14]. ATIGIT blockade alone increases IFNg production in circulating NK cells, but has to be used in combination with IL-15 to promote increased cytotoxicity in tumour infiltrating NK cells [30]. bNKp44 is classified as an activating receptor, but can have inhibitory effects when engaged with inhibitory ligands such as PCNA [40]
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