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Harnessing natural killer cells for cancer immunotherapy: dispatching the first responders

Nature Reviews Drug Discovery volume 21, pages 559–577 (2022)Cite this article

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Abstract

Natural killer (NK) cells have crucial roles in the innate immunosurveillance of cancer and viral infections. They are ‘first responders’ that can spontaneously recognize abnormal cells in the body, rapidly eliminate them through focused cytotoxicity mechanisms and potently produce pro-inflammatory cytokines and chemokines that recruit and activate other immune cells to initiate an adaptive response. From the initial discovery of the diverse cell surface receptors on NK cells to the characterization of regulatory events that control their function, our understanding of the basic biology of NK cells has improved dramatically in the past three decades. This advanced knowledge has revealed increased mechanistic complexity, which has opened the doors to the development of a plethora of exciting new therapeutics that can effectively manipulate and target NK cell functional responses, particularly in cancer patients. Here, we summarize the basic mechanisms that regulate NK cell biology, review a wide variety of drugs, cytokines and antibodies currently being developed and used to stimulate NK cell responses, and outline evolving NK cell adoptive transfer approaches to treat cancer.

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Fig. 1: KIRs provide diversity, tolerance and education to human NK cells.
Fig. 2: Antibodies in NK cell immunotherapy.
Fig. 3: Different strategies for producing bispecific or trispecific antibody constructs.

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Acknowledgements

The authors appreciate funding from a Health Research Formula Fund grant from the Commonwealth of Pennsylvania (CURE; to K.S.C.), NIH grants AI148117 (K.S.C.) and CA194263 (K.S.C.), NCI NIH training grant T32 CA9035 (N.A.M.) and NCI Comprehensive Cancer Center support grant CA06927 (FCCC).

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  1. Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, PA, USA

    Nicholas A. Maskalenko, Dmitry Zhigarev & Kerry S. Campbell

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  3. Kerry S. Campbell
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The authors contributed equally to all aspects of the article.

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Correspondence to Kerry S. Campbell.

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K.S.C. has received research support from Janssen Pharma, Genentech, Horizon Pharma, ImmunityBio and Immune Oncology Biosciences, consulting fees from Immunitas and Tavotec, and has patents with ImmunityBio. The other authors declare no competing interests.

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Glossary

Opsonization

The binding of antibodies to the surface of a pathogen or tumour cell, which are recognized by Fc receptors on phagocytes to facilitate antibody-dependent cellular phagocytosis or by CD16 on natural killer cells to trigger antibody-dependent cellular cytotoxicity.

Tolerize

The process by which normal cells induce tolerance towards natural killer cell-mediated attack by expressing major histocompatibility complex class I molecules that engage inhibitory receptors, such as killer cell inhibitory receptor (KIR).

Fucosylation

The process of covalently attaching the sugar fucose to IgG molecules as a post-translational event, which reduces the affinity of IgG1 or IgG3 to bind CD16 and thereby decreases their potency in stimulating antibody-dependent cellular cytotoxicity by natural killer cells.

Fratricide

Classically defined as killing one’s sibling, this term has been used to define the process by which natural killer cells sometimes aberrantly attack and kill each other.

Feeder cell lines

Cell lines that are used to stimulate the ex vivo proliferation of natural killer (NK) cells and are generally chosen for low surface expression of major histocompatibility complex class I and/or engineered to express surface bound cytokines or ligands for NK cell-activating receptors.

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Maskalenko, N.A., Zhigarev, D. & Campbell, K.S. Harnessing natural killer cells for cancer immunotherapy: dispatching the first responders. Nat Rev Drug Discov 21, 559–577 (2022). https://doi.org/10.1038/s41573-022-00413-7

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