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
; 147(1): 349-360, 2021 01.
Article
en En
| MEDLINE
| ID: mdl-32417134
ABSTRACT
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.Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Células Asesinas Naturales
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Regulación Neoplásica de la Expresión Génica
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Interleucina-2
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Interleucina-15
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Interleucina-18
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Microambiente Tumoral
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Receptor de Muerte Celular Programada 1
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Glucocorticoides
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Proteínas de Neoplasias
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Neoplasias
Límite:
Humans
Idioma:
En
Año:
2021
Tipo del documento:
Article