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Minimal PD-1 expression in mouse and human NK cells under diverse conditions
Sean J. Judge, … , Robert J. Canter, William J. Murphy
Sean J. Judge, … , Robert J. Canter, William J. Murphy
Published March 5, 2020
Citation Information: J Clin Invest. 2020;130(6):3051-3068. https://doi.org/10.1172/JCI133353.
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Research Article Immunology

Minimal PD-1 expression in mouse and human NK cells under diverse conditions

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Abstract

PD-1 expression is a hallmark of both early antigen-specific T cell activation and later chronic stimulation, suggesting key roles in both naive T cell priming and memory T cell responses. Although significant similarities exist between T cells and NK cells, there are critical differences in their biology and functions reflecting their respective adaptive and innate immune effector functions. Expression of PD-1 on NK cells is controversial despite rapid incorporation into clinical cancer trials. Our objective was to stringently and comprehensively assess expression of PD-1 on both mouse and human NK cells under multiple conditions and using a variety of readouts. We evaluated NK cells from primary human tumor samples, after ex vivo culturing, and from multiple mouse tumor and viral models using flow cytometry, quantitative reverse-transcriptase PCR (qRT-PCR), and RNA-Seq for PD-1 expression. We demonstrate that, under multiple conditions, human and mouse NK cells consistently lack PD-1 expression despite the marked upregulation of other activation/regulatory markers, such as TIGIT. This was in marked contrast to T cells, which were far more prominent within all tumors and expressed PD-1. These data have important implications when attempting to discern NK from T cell effects and to determine whether PD-1 targeting can be expected to have direct effects on NK cell functions.

Authors

Sean J. Judge, Cordelia Dunai, Ethan G. Aguilar, Sarah C. Vick, Ian R. Sturgill, Lam T. Khuat, Kevin M. Stoffel, Jonathan Van Dyke, Dan L. Longo, Morgan A. Darrow, Stephen K. Anderson, Bruce R. Blazar, Arta M. Monjazeb, Jonathan S. Serody, Robert J. Canter, William J. Murphy

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Figure 2

Mouse intratumoral NK cells do not upregulate PD-1.

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Mouse intratumoral NK cells do not upregulate PD-1.
(A) Gating strategy ...
(A) Gating strategy for analysis of intratumoral NK and T cells from CT26 tumors in BALB/c mice. (B) Total cells present, (C) percentage of live cells in tumor, (D) and percentage of live cells in tumor represented by NK and T cells. (E and F) NK cells in CT26 tumors show significantly increased expression of activation marker CD69 and functional marker granzyme B compared with splenic NK cells. (G) Representative NK cell (CD3–NKp46+) and T cell (CD3+NK1.1–) parent gating shows the expression of PD-1 on NK and T cells for CT26 SC tumors. (H) Aggregate expression across tumor models shows consistently minimal expression of PD-1 on NK cells, with significantly higher expression on T cells. (I) Schematic for generating and isolating intratumoral NK and T cells from CT26 tumor–bearing BALB/c mice and (J) RNA-Seq analysis of intratumoral NK and T cells. (K) PD-1 reporter mice were implanted with SC CT26 tumors and analyzed for PD-1 expression. Using the reporter system, PD-1 expression on intratumoral NK cells remains minimal compared with that in T cells, as seen by representative flow plots and (L) summary data. (A–H) Data are shown as mean ± SD for n = 3–14 mice/group and are representative of 2 to 3 independent experiments. (I and J) Tumors pooled from n = 4 (no. 1) and n = 6 (no. 2) mice/group. (K and L) Data are shown as mean ± SD for n = 3 mice/group. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001, paired Student’s t test.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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