Adaptive NK cells resist regulatory T-cell suppression driven by IL37

Dhifaf Akef Sarhan, Keli L Hippen, Amanda Lemire, Skyler Hying, Xianghua Luo, Todd R Lenvik, Julie M Curtsinger, Zachary B Davis, Bin Zhang, Sarah A Cooley, Frank M Cichocki, Bruce R Blazar, Jeffrey S Miller

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Natural killer (NK) cells are capable of fighting viral infections and cancer. However, these responses are inhibited by immune suppressor cells in the tumor microenvironment. Tumor progression promotes the recruitment and generation of intratumoral regulatory T cells (Treg), associated with a poor prognosis in cancer patients. Here, we show that canonical NK cells are highly susceptible to Treg-mediated suppression, in contrast to highly resistant CD57 þ FceRgNKG2C þ adaptive (CD56 þ CD3) NK cells that expand in cytomegalovirus exposed individuals. Specifically, Tregs suppressed canonical but not adaptive NK-cell proliferation, IFNg production, degranulation, and cytotoxicity. Treg-mediated suppression was associated with canonical NK-cell downregulation of TIM3, a receptor that activates NK-cell IFNg production upon ligand engagement, and upregulation of the NK-cell inhibitory receptors PD-1 and the IL1 receptor family member, IL1R8 (SIGIRR or TIR8). Treg production of the IL1R8 ligand, IL37, contributed to the phenotypic changes and diminished function in Treg-suppressed canonical NK cells. Blocking PD-1, IL1R8, or IL37 abrogated Treg suppression of canonical NK cells while maintaining NK-cell TIM3 expression. Our data uncover new mechanisms of Treg-mediated suppression of canonical NK cells and identify that adaptive NK cells are inherently resistant to Treg suppression. Strategies to enhance the frequency of adaptive NK cells in the tumor microenvironment or to blunt Treg suppression of canonical NK cells will enhance the efficacy of NK-cell cancer immunotherapy.

Original languageEnglish (US)
Pages (from-to)766-775
Number of pages10
JournalCancer Immunology Research
Volume6
Issue number7
DOIs
StatePublished - Jul 1 2018

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Regulatory T-Lymphocytes
Natural Killer Cells
Natural Killer Cell Receptors
Tumor Microenvironment
Programmed Cell Death 1 Receptor
Neoplasms
Ligands
Interleukin-1 Receptors
Virus Diseases
Cytomegalovirus
Immunotherapy
Up-Regulation
Down-Regulation
Cell Proliferation

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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Adaptive NK cells resist regulatory T-cell suppression driven by IL37. / Sarhan, Dhifaf Akef; Hippen, Keli L; Lemire, Amanda; Hying, Skyler; Luo, Xianghua; Lenvik, Todd R; Curtsinger, Julie M; Davis, Zachary B; Zhang, Bin; Cooley, Sarah A; Cichocki, Frank M; Blazar, Bruce R; Miller, Jeffrey S.

In: Cancer Immunology Research, Vol. 6, No. 7, 01.07.2018, p. 766-775.

Research output: Contribution to journalArticle

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abstract = "Natural killer (NK) cells are capable of fighting viral infections and cancer. However, these responses are inhibited by immune suppressor cells in the tumor microenvironment. Tumor progression promotes the recruitment and generation of intratumoral regulatory T cells (Treg), associated with a poor prognosis in cancer patients. Here, we show that canonical NK cells are highly susceptible to Treg-mediated suppression, in contrast to highly resistant CD57 {\th} FceRgNKG2C {\th} adaptive (CD56 {\th} CD3) NK cells that expand in cytomegalovirus exposed individuals. Specifically, Tregs suppressed canonical but not adaptive NK-cell proliferation, IFNg production, degranulation, and cytotoxicity. Treg-mediated suppression was associated with canonical NK-cell downregulation of TIM3, a receptor that activates NK-cell IFNg production upon ligand engagement, and upregulation of the NK-cell inhibitory receptors PD-1 and the IL1 receptor family member, IL1R8 (SIGIRR or TIR8). Treg production of the IL1R8 ligand, IL37, contributed to the phenotypic changes and diminished function in Treg-suppressed canonical NK cells. Blocking PD-1, IL1R8, or IL37 abrogated Treg suppression of canonical NK cells while maintaining NK-cell TIM3 expression. Our data uncover new mechanisms of Treg-mediated suppression of canonical NK cells and identify that adaptive NK cells are inherently resistant to Treg suppression. Strategies to enhance the frequency of adaptive NK cells in the tumor microenvironment or to blunt Treg suppression of canonical NK cells will enhance the efficacy of NK-cell cancer immunotherapy.",
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AU - Sarhan, Dhifaf Akef

AU - Hippen, Keli L

AU - Lemire, Amanda

AU - Hying, Skyler

AU - Luo, Xianghua

AU - Lenvik, Todd R

AU - Curtsinger, Julie M

AU - Davis, Zachary B

AU - Zhang, Bin

AU - Cooley, Sarah A

AU - Cichocki, Frank M

AU - Blazar, Bruce R

AU - Miller, Jeffrey S

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N2 - Natural killer (NK) cells are capable of fighting viral infections and cancer. However, these responses are inhibited by immune suppressor cells in the tumor microenvironment. Tumor progression promotes the recruitment and generation of intratumoral regulatory T cells (Treg), associated with a poor prognosis in cancer patients. Here, we show that canonical NK cells are highly susceptible to Treg-mediated suppression, in contrast to highly resistant CD57 þ FceRgNKG2C þ adaptive (CD56 þ CD3) NK cells that expand in cytomegalovirus exposed individuals. Specifically, Tregs suppressed canonical but not adaptive NK-cell proliferation, IFNg production, degranulation, and cytotoxicity. Treg-mediated suppression was associated with canonical NK-cell downregulation of TIM3, a receptor that activates NK-cell IFNg production upon ligand engagement, and upregulation of the NK-cell inhibitory receptors PD-1 and the IL1 receptor family member, IL1R8 (SIGIRR or TIR8). Treg production of the IL1R8 ligand, IL37, contributed to the phenotypic changes and diminished function in Treg-suppressed canonical NK cells. Blocking PD-1, IL1R8, or IL37 abrogated Treg suppression of canonical NK cells while maintaining NK-cell TIM3 expression. Our data uncover new mechanisms of Treg-mediated suppression of canonical NK cells and identify that adaptive NK cells are inherently resistant to Treg suppression. Strategies to enhance the frequency of adaptive NK cells in the tumor microenvironment or to blunt Treg suppression of canonical NK cells will enhance the efficacy of NK-cell cancer immunotherapy.

AB - Natural killer (NK) cells are capable of fighting viral infections and cancer. However, these responses are inhibited by immune suppressor cells in the tumor microenvironment. Tumor progression promotes the recruitment and generation of intratumoral regulatory T cells (Treg), associated with a poor prognosis in cancer patients. Here, we show that canonical NK cells are highly susceptible to Treg-mediated suppression, in contrast to highly resistant CD57 þ FceRgNKG2C þ adaptive (CD56 þ CD3) NK cells that expand in cytomegalovirus exposed individuals. Specifically, Tregs suppressed canonical but not adaptive NK-cell proliferation, IFNg production, degranulation, and cytotoxicity. Treg-mediated suppression was associated with canonical NK-cell downregulation of TIM3, a receptor that activates NK-cell IFNg production upon ligand engagement, and upregulation of the NK-cell inhibitory receptors PD-1 and the IL1 receptor family member, IL1R8 (SIGIRR or TIR8). Treg production of the IL1R8 ligand, IL37, contributed to the phenotypic changes and diminished function in Treg-suppressed canonical NK cells. Blocking PD-1, IL1R8, or IL37 abrogated Treg suppression of canonical NK cells while maintaining NK-cell TIM3 expression. Our data uncover new mechanisms of Treg-mediated suppression of canonical NK cells and identify that adaptive NK cells are inherently resistant to Treg suppression. Strategies to enhance the frequency of adaptive NK cells in the tumor microenvironment or to blunt Treg suppression of canonical NK cells will enhance the efficacy of NK-cell cancer immunotherapy.

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