TGF-β–inducible microRNA-183 silences tumor-associated natural killer cells
Menée in vitro et à partir d'échantillons tumoraux prélevés sur 29 patients atteints d'un cancer du poumon, cette étude met en évidence des mécanismes par lesquels un micro-ARN induit par le facteur TGF-β, miR-183, réprime l'expression de la protéine DAP12 dans les cellules NK du micro-environnement tumoral
Transforming growth factor β1 (TGF-β), enriched in the tumor microenvironment and broadly immunosuppressive, inhibits natural killer (NK) cell function by yet-unknown mechanisms. Here we show that TGF-β–treated human NK cells exhibit reduced tumor cytolysis and abrogated perforin polarization to the immune synapse. This result was accompanied by loss of surface expression of activating killer Ig-like receptor 2DS4 and NKp44, despite intact cytoplasmic stores of these receptors. Instead, TGF-β depleted DNAX activating protein 12 kDa (DAP12), which is critical for surface NK receptor stabilization and downstream signal transduction. Mechanistic analysis revealed that TGF-β induced microRNA (miR)-183 to repress DAP12 transcription/translation. This pathway was confirmed with luciferase reporter constructs bearing the DAP12 3′ untranslated region as well as in human NK cells by use of sense and antisense miR-183. Moreover, we documented reduced DAP12 expression in tumor-associated NK cells in lung cancer patients, illustrating this pathway to be consistently perturbed in the human tumor microenvironment.