Killer instincts: natural killer cells as multifactorial cancer immunotherapy

Sarah Nersesian; Emily B Carter; Stacey N Lee; Lauren P Westhaver; Jeanette E Boudreau

doi:10.3389/fimmu.2023.1269614

Killer instincts: natural killer cells as multifactorial cancer immunotherapy

Front Immunol. 2023 Nov 28:14:1269614. doi: 10.3389/fimmu.2023.1269614. eCollection 2023.

Authors

Sarah Nersesian^{1

2}, Emily B Carter^{1

2}, Stacey N Lee^{1

2}, Lauren P Westhaver³, Jeanette E Boudreau^{1

2

3}

Affiliations

¹ Department of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada.
² Beatrice Hunter Cancer Research Institute, Halifax, NS, Canada.
³ Department of Pathology, Dalhousie University, Halifax, NS, Canada.

Abstract

Natural killer (NK) cells integrate heterogeneous signals for activation and inhibition using germline-encoded receptors. These receptors are stochastically co-expressed, and their concurrent engagement and signaling can adjust the sensitivity of individual cells to putative targets. Against cancers, which mutate and evolve under therapeutic and immunologic pressure, the diversity for recognition provided by NK cells may be key to comprehensive cancer control. NK cells are already being trialled as adoptive cell therapy and targets for immunotherapeutic agents. However, strategies to leverage their naturally occurring diversity and agility have not yet been developed. In this review, we discuss the receptors and signaling pathways through which signals for activation or inhibition are generated in NK cells, focusing on their roles in cancer and potential as targets for immunotherapies. Finally, we consider the impacts of receptor co-expression and the potential to engage multiple pathways of NK cell reactivity to maximize the scope and strength of antitumor activities.

Keywords: cancer immunotherapy; innate lymphoid cells; killer immunoglobulin-like receptors (KIR); natural killer cells; signal integration.

Publication types

Review
Research Support, Non-U.S. Gov't

MeSH terms

Humans
Immunotherapy
Instinct*
Killer Cells, Natural
Neoplasms* / therapy

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. SN, EC and SL are trainee members of the Beatrice Hunter Cancer Research Institute. SN is supported by a Vanier Canada Graduate Scholarship from the Canadian Institutes of Health Research and a Killam Predoctoral Award and Nova Scotia Graduate Scholarship through Dalhousie University. EC has funds provided by the Dalhousie Medical Research Foundation’s Crease Endowment for Cancer Research. SL is supported by a Canada Graduate Scholarship from the Canadian Institutes of Health Research and a Nova Scotia Graduate Scholarship through Dalhousie University. This work is supported by a joint J.D. Irving/Canadian Cancer Society grant co-funded by the Canadian Institutes of Health Research and the Cancer Research Society’s operating grant to JB.