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
Linda Quatrini, Paola Vacca, Nicola Tumino, Francesca Besi, Anna Laura Di Pace, Francesca Scordamaglia, Stefania Martini, Enrico Munari, Maria Cristina Mingari, Sophie Ugolini, Lorenzo Moretta
Abstract
BackgroundProgrammed 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.ObjectiveWe 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.MethodsNK 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.ResultsGlucocorticoids 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.ConclusionsThese results provide evidence of a novel immune suppressive mechanism of glucocorticoids involving the transcriptional and translational control of an important immune checkpoint. 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. 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. 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. 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. These results provide evidence of a novel immune suppressive mechanism of glucocorticoids involving the transcriptional and translational control of an important immune checkpoint.