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Roles of natural killer cells in immunity to cancer, and applications to immunotherapy

Abstract

Great strides have been made in recent years towards understanding the roles of natural killer (NK) cells in immunity to tumours and viruses. NK cells are cytotoxic innate lymphoid cells that produce inflammatory cytokines and chemokines. By lysing transformed or infected cells, they limit tumour growth and viral infections. Whereas T cells recognize peptides presented by MHC molecules, NK cells display receptors that recognize stress-induced autologous proteins on cancer cells. At the same time, their functional activity is inhibited by MHC molecules displayed on such cells. The enormous potential of NK cells for immunotherapy for cancer is illustrated by their broad recognition of stressed cells regardless of neoantigen presentation, and enhanced activity against tumours that have lost expression of MHC class I owing to acquired resistance mechanisms. As a result, many efforts are under way to mobilize endogenous NK cells with therapeutics, or to provide populations of ex vivo-expanded NK cells as a cellular therapy, in some cases by equipping the NK cells with chimeric antigen receptors. Here we consider the key features that underlie why NK cells are emerging as important new additions to the cancer therapeutic arsenal.

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Fig. 1: NK cell function is regulated by cell surface receptors and cytokines.
Fig. 2: Influences of the tumour microenvironment on NK cell activation, inhibition and inactivation.
Fig. 3: Immunotherapeutic approaches to mobilize antitumour responses by NK cells.

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Acknowledgements

Research in the authors’ laboratory was supported by US National Institute of Health grant R01AI113041 (D.H.R.) and the University of California, Berkeley Immunotherapeutics and Vaccine Research Initiative supported by Aduro Biotech (045535 and 045538) (D.H.R.). N.K.W. was supported by a US National Science Foundation predoctoral fellowship (DGE 1752814) and a QB3 Frontiers in Medical Research predoctoral fellowship. D.U.K. was supported by a predoctoral fellowship from the Cancer Research Coordinating Committee of the University of California.

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D.H.R. cofounded Dragonfly Therapeutics and served or serves on the scientific advisory boards of Dragonfly Therapeutics, Aduro Biotech and Innate Pharma; he has a financial interest in all three companies and could benefit from commercialization of the results of his research in cancer immunology. The other authors declare that they have no competing interests.

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Wolf, N.K., Kissiov, D.U. & Raulet, D.H. Roles of natural killer cells in immunity to cancer, and applications to immunotherapy. Nat Rev Immunol (2022). https://doi.org/10.1038/s41577-022-00732-1

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