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Molecular checkpoints controlling natural killer cell activation and their modulation for cancer immunotherapy

Hyung-Joon Kwon,Nayoung Kim,H. Kim

Published 2017 in Experimental and Molecular Medicine

ABSTRACT

Natural killer (NK) cells have gained considerable attention as promising therapeutic tools for cancer therapy due to their innate selectivity against cancer cells over normal healthy cells. With an array of receptors evolved to sense cellular alterations, NK cells provide early protection against cancer cells by producing cytokines and chemokines and exerting direct cytolytic activity. These effector functions are governed by signals transmitted through multiple receptor–ligand interactions but are not achieved by engaging a single activating receptor on resting NK cells. Rather, they require the co-engagement of different activating receptors that use distinct signaling modules, due to a cell-intrinsic inhibition mechanism. The redundancy of synergizing receptors and the inhibition of NK cell function by a single class of inhibitory receptor suggest the presence of common checkpoints to control NK cell activation through different receptors. These molecular checkpoints would be therapeutically targeted to harness the power of NK cells against diverse cancer cells that express heterogeneous ligands for NK cell receptors. Recent advances in understanding the activation of NK cells have revealed promising candidates in this category. Targeting such molecular checkpoints will facilitate NK cell activation by lowering activation thresholds, thereby providing therapeutic strategies that optimize NK cell reactivity against cancer. Investigating how natural killer (NK) cells are activated could provide a basis for developing novel NK cell—based cancer therapies. NK cells, which are part of the body's cancer surveillance system, are white blood cells that are primed to selectively kill tumor cells. Given their “ready-to-kill” state, they are tightly controlled and require more than one signal for activation. Although NK cells have been investigated for use in cancer therapy, most research to date has focused on inhibitory signaling. Hun Sik Kim, Nayoung Kim and Hyung-Joon Kwon at the University of Ulsan College of Medicine in Seoul, Korea, have published a review of recent research on activation of NK cells, highlighting so-called ‘checkpoint’ molecules that integrate signals from different pathways. Understanding these molecular checkpoints could reveal ways to leverage NK cells' ability to target cancer cells.

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