Programmed cell death protein 1 on natural killer cells: fact or fiction?
Monica M. Cho, Aicha E. Quamine, Mallery R. Olsen, Christian M. Capitini
Monica M. Cho, Aicha E. Quamine, Mallery R. Olsen, Christian M. Capitini
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Commentary

Programmed cell death protein 1 on natural killer cells: fact or fiction?

Abstract

Programmed cell death protein 1 (PD-1) has become one of the most investigated targets for cancer immunotherapy. Most research has centered on inhibiting PD-1 on T cells, but there is increased interest in understanding the role of PD-1 on NK cells. While the expression of PD-1 on NK cells has been controversial, with papers publishing contradictory results in multiple models, there is increased clinical interest in NK and PD-1 immunotherapy. In this issue of the JCI, Judge et al. comprehensively explore the lack of PD-1 expression on murine, canine, and human NK cells and the clinical implication of these findings.

Authors

Monica M. Cho, Aicha E. Quamine, Mallery R. Olsen, Christian M. Capitini

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Figure 1

Potential mechanisms of PD-1 expression on NK cells and anti–PD-1 treatment.

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Potential mechanisms of PD-1 expression on NK cells and anti–PD-1 treatm...
(i) When activating receptors on NK cells engage with ligands on tumor cells, cytokine receptors with cytokines or viral receptors with associated viruses. (ii) PD-1 mRNA and splice variants may (or may not) lead to PD-1 protein cell surface expression. (iii) NK cell apoptosis can result in release of a nuclear antigen that can be mistaken for PD-1. While NK cells may inherently minimally express PD-1, even after activation, NK cells could acquire PD-1 through (iv) uptake of extracellular vesicles released from T cells or by trogocytosis upon contact with a neighboring T cell within the tumor microenvironment. (v) False-positive results could result from anti–PD-1 labeling a currently unidentified cell surface homolog of PD-1 on NK cells. Benefits from anti–PD-1 checkpoint blockade could also result from anti–PD-1 binding a homolog on the tumor cell, which instead of preventing exhaustion in the NK cells, in fact, stimulates antibody-dependent cellular cytotoxicity (ADCC).