NK Cells in Cancer Immunotherapy
Walter and Eliza Hall Institute
1g Royal Parade
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The past decade has seen a revolution in cancer treatment in the form of immunotherapy. This revolution is a result of translating our extensive understanding of T cell biology into the development of immune “checkpoint” inhibitor antibodies that primarily function by blocking inhibitory pathways in tumour antigen-specific T cells within the tumour microenvironment. Although closely related to T lymphocytes, Natural Killer (NK) cell development is unique in the sense that NK cells do not undergo positive or negative selection yet do not react against healthy self-tissue resulting in autoimmune diseases. In contrast, NK cells react strongly against transformed self-tissue and are key effectors in tumour immunity. T cell homeostasis is tightly regulated by cytokine levels and rearranged antigen receptor stimulation however the lack of rearranged antigen receptors on NK cells asks several questions about how NK cell numbers and activity are regulated during health and disease. We hypothesise that NK cell homeostasis and tolerance are governed by several intrinsic regulatory pathways (termed the NK cell homeostasis triad) and local IL-15 levels that synergise to limit NK cell frequency/activity during health but are overcome during tumour immune responses to permit a potent localised response with little risk of auto-inflammation. As such, we hypothesise that genetic perturbation of one member of the NK cell homeostasis triad is insufficient to break NK cell tolerance in steady-state but NK cell tolerance is consistently broken during cancer and that breaking NK cell tolerance or reducing the threshold to break NK cell tolerance is a key strategy in NK cell cancer immunotherapy.
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