Natural Killer Cells in Cancer Immunotherapy

Jeffrey S Miller,Lewis L Lanier

doi:10.1146/annurev-cancerbio-030518-055653

Jeffrey S Miller, Lewis L Lanier

Open Access

https://doi.org/10.1146/annurev-cancerbio-030518-055653

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Abstract

Natural killer (NK) cells have evolved to complement T and B cells in host defense against pathogens and cancer. They recognize infected cells and tumors using a sophisticated array of activating, costimulatory, and inhibitory receptors that are expressed on NK cell subsets to create extensive functional diversity. NK cells can be targeted to kill with exquisite antigen specificity by antibody-dependent cellular cytotoxicity. NK and T cells share many of the costimulatory and inhibitory receptors that are currently under evaluation in the clinic for cancer immunotherapy. As with T cells, genetic engineering is being employed to modify NK cells to specifically target them to tumors and to enhance their effector functions. As the selective pressures exerted by immunotherapies to augment CD8+T cell responses may result in loss of MHC class I, NK cells may provide an important fail-safe to eliminate these tumors by their capacity to eliminate tumors that are “missing self.”

Highlights

The ability of lymphocytes to mediate natural killing of certain tumors and virus-infected cells was first discovered by several laboratories in the 1970s (Herberman et al 1975, Kiessling et al 1975, Ortaldo et al 1977)
natural killer (NK) cells and all innate lymphoid cell (ILC) are distinct from T cells in that they do not productively rearrange or express T cell antigen receptor genes, and they develop in mice lacking the Rag1 and Rag2 genes required for the development of T cells and B cells
While NK cells are most similar in function to CD8+ cytotoxic T lymphocytes in their ability to directly recognize and kill tumors and pathogen-infected cells by mechanisms using granzymes, perforin, and TNF family death effector molecules (Sun & Lanier 2011), ILC1, ILC2, and ILC3 are considered functional counterparts of the Th1, Th2, and Th17 subsets of CD4+ T cells based on their secretion of characteristic cytokines and the requirement of certain transcription factors for development (Klose & Artis 2016)

Summary

INTRODUCTION

The ability of lymphocytes to mediate natural killing of certain tumors and virus-infected cells was first discovered by several laboratories in the 1970s (Herberman et al 1975, Kiessling et al 1975, Ortaldo et al 1977). Studies in mice and humans have identified subsets of NK cells that possess immunological memory and have been termed “memory” or “adaptive” NK cells (O’Sullivan et al 2015) In humans, this subset of adaptive NK cells that have been expanded by cytomegalovirus (CMV) infection has been shown to lack expression of the FcεRIγ signaling protein (Zhang et al 2013) and to have undergone epigenetic modification, resulting in NK cells with enhanced antibody-dependent cellular. NK cells express several receptors that transmit intracellular activating signals by their association with ITAM-bearing adapter proteins, including FcεRIγ, CD3ζ, and DAP12. Upon receptor engagement, these adapters recruit the Syk or ZAP70 tyrosine kinases and initiate downstream activation, similar to the T cell antigen receptor or surface immunoglobulin in T and B cells. The precise nature of these NCR ligands on tumors has proven www.annualreviews.org NK Cells in Cancer Immunotherapy 79

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PERSPECTIVES AND CONCLUSIONS

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DISCLOSURE STATEMENT