Glucocorticoids and the cytokines IL-12, IL-15, and IL-18 present in the tumor microenvironment induce PD-1 expression on human natural killer cells

J Allergy Clin Immunol. 2021 Jan;147(1):349-360. doi: 10.1016/j.jaci.2020.04.044. Epub 2020 May 14.


Background: Programmed cell death protein 1 (PD-1)-immune checkpoint blockade has provided significant clinical efficacy across various types of cancer by unleashing both T and natural killer (NK) cell-mediated antitumor responses. However, resistance to immunotherapy occurs for many patients, rendering the identification of the mechanisms that control PD-1 expression extremely important to increase the response to the therapy.

Objective: We sought to identify the stimuli and the molecular mechanisms that induce the de novo PD-1 expression on human NK cells in the tumor setting.

Methods: NK cells freshly isolated from peripheral blood of healthy donors were stimulated with different combinations of molecules, and PD-1 expression was studied at the mRNA and protein levels. Moreover, ex vivo analysis of tumor microenvironment and NK cell phenotype was performed.

Results: Glucocorticoids are indispensable for PD-1 induction on human NK cells, in cooperation with a combination of cytokines that are abundant at the tumor site. Mechanistically, glucocorticoids together with IL-12, IL-15, and IL-18 not only upregulate PDCD1 transcription, but also activate a previously unrecognized transcriptional program leading to enhanced mRNA translation and resulting in an increased PD-1 amount in NK cells.

Conclusions: These results provide evidence of a novel immune suppressive mechanism of glucocorticoids involving the transcriptional and translational control of an important immune checkpoint.

Keywords: NK cells; PD-1; cancer immunology; glucocorticoids; immune checkpoint; immunotherapy; translational control.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Gene Expression Regulation, Neoplastic / immunology*
  • Glucocorticoids / immunology*
  • Humans
  • Interleukin-15 / immunology*
  • Interleukin-18 / immunology*
  • Interleukin-2 / immunology*
  • K562 Cells
  • Killer Cells, Natural / immunology*
  • Neoplasm Proteins / immunology*
  • Neoplasms / immunology*
  • Programmed Cell Death 1 Receptor / immunology*
  • Tumor Microenvironment / immunology*


  • Glucocorticoids
  • IL15 protein, human
  • IL18 protein, human
  • IL2 protein, human
  • Interleukin-15
  • Interleukin-18
  • Interleukin-2
  • Neoplasm Proteins
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor