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