Balanced engagement of activating and inhibitory receptors mitigates human NK cell exhaustion

Jacob A. Myers; Dawn Schirm; Laura Bendzick; Rachel Hopps; Carly Selleck; Peter Hinderlie; Martin Felices; Jeffrey S. Miller

doi:10.1172/jci.insight.150079

Balanced engagement of activating and inhibitory receptors mitigates human NK cell exhaustion

Jacob A. Myers,¹ Dawn Schirm,¹ Laura Bendzick,¹ Rachel Hopps,¹ Carly Selleck,¹ Peter Hinderlie,¹ Martin Felices,¹ and Jeffrey S. Miller²

Published June 21, 2022 - More info

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Abstract

Natural killer (NK) cell exhaustion is caused by chronic exposure to activating stimuli during viral infection, tumorigenesis, and prolonged cytokine treatment. Evidence suggests that exhaustion may play a role in disease progression, however relative to T cell exhaustion, the mechanisms underlying NK cell exhaustion and methods of reversing it are poorly understood. Here, we describe a novel in vitro model of exhaustion that employs plate-bound agonists of the NK cell activating receptors NKp46 and NKG2D to induce canonical exhaustion phenotypes. In this model, prolonged activation results in downregulation of activating receptors, upregulation of checkpoint markers, decreased cytokine production and cytotoxicity in vitro, defects in glycolytic metabolism, and decreased persistence, function, and tumor control in vivo. Furthermore, we discover a beneficial effect of NK cell inhibitory receptor signaling during exhaustion. By simultaneously engaging the inhibitory receptor NKG2A during activation in our model, cytokine production and cytotoxicity defects can be mitigated, suggesting that balancing positive and negative signals integrated by effector NK cells can be beneficial for anti-tumor immunity. Together, these data uncover some of the mechanisms underlying NK cell exhaustion in humans and establish our novel in vitro model as a valuable tool for studying the processes regulating exhaustion.

Balanced engagement of activating and inhibitory receptors mitigates human NK cell exhaustion

Jacob A. Myers,¹ Dawn Schirm,¹ Laura Bendzick,¹ Rachel Hopps,¹ Carly Selleck,¹ Peter Hinderlie,¹ Martin Felices,¹ and Jeffrey S. Miller²

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Balanced engagement of activating and inhibitory receptors mitigates human NK cell exhaustion

Jacob A. Myers,1 Dawn Schirm,1 Laura Bendzick,1 Rachel Hopps,1 Carly Selleck,1 Peter Hinderlie,1 Martin Felices,1 and Jeffrey S. Miller2

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Jacob A. Myers,¹ Dawn Schirm,¹ Laura Bendzick,¹ Rachel Hopps,¹ Carly Selleck,¹ Peter Hinderlie,¹ Martin Felices,¹ and Jeffrey S. Miller²