ADORA1 Inhibition Promotes Tumor Immune Evasion by Regulating the ATF3-PD-L1 Axis
Menée à l'aide de lignées cellulaires de mélanome humain, de modèles murins et de tissus tumoraux issus de patients atteints d'un carcinome du poumon non à petites cellules, cette étude met en évidence un mécanisme par lequel l'inhibition du récepteur ADORA1 favorise l'échappement immunitaire de la tumeur en régulant la voie impliquant le facteur de transcription ATF3 et la protéine PD-L1
Here, we show that tumor ADORA1 deletion suppresses cell growth in human melanoma cell lines in vitro and tumor development in vivo in immune-deficient xenografts. However, this deletion induces the upregulation of PD-L1 levels, which inactivates cocultured T cells in vitro, compromises anti-tumor immunity in vivo, and reduces anti-tumor efficacy in an immune-competent mouse model. Functionally, PD-1 mAb treatment enhances the efficacy of ADORA1-deficient or ADORA1 antagonist-treated melanoma and NSCLC immune-competent mouse models. Mechanistically, we identify ATF3 as the factor transcriptionally upregulating PD-L1 expression. Tumor ATF3 deletion improves the effect of ADORA1 antagonist treatment of melanoma and NSCLC xenografts. We observe higher ADORA1, lower ATF3, and lower PD-L1 expression levels in tumor tissues from nonresponders among PD-1 mAb-treated NSCLC patients.