ADORA1 Inhibition Promotes Tumor Immune Evasion by Regulating the ATF3-PD-L1 Axis

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Adenosine receptor 1 (ADORA1) plays a role in tumor progression.
• PD-L1 expression on tumors can suppress anti-tumor immune responses.

Purpose of the Study:

• To investigate the role of ADORA1 in melanoma and NSCLC.
• To explore the relationship between ADORA1, PD-L1, and anti-tumor immunity.
• To evaluate therapeutic strategies targeting ADORA1 and PD-1/PD-L1.

Main Methods:

• In vitro and in vivo studies using human melanoma cell lines and xenografts.
• Analysis of PD-L1 and ATF3 expression.
• Treatment with ADORA1 antagonists and PD-1 monoclonal antibodies (mAbs).
• Studies in immune-deficient and immune-competent mouse models.

Main Results:

• Tumor ADORA1 deletion suppressed cell growth but upregulated PD-L1.
• Upregulated PD-L1 inactivated T cells and compromised anti-tumor immunity.
• PD-1 mAb treatment enhanced efficacy in ADORA1-deficient or antagonist-treated models.
• ATF3 was identified as a transcriptional regulator of PD-L1.
• Tumor ATF3 deletion improved ADORA1 antagonist efficacy.
• Nonresponders to PD-1 mAb therapy showed higher ADORA1 and lower ATF3/PD-L1 expression.

Conclusions:

• ADORA1 deletion promotes an immunosuppressive tumor microenvironment via PD-L1 upregulation.
• Combined targeting of ADORA1 and PD-1/PD-L1 pathways, potentially modulated by ATF3, offers a promising therapeutic strategy for melanoma and NSCLC.
• Biomarker analysis suggests ADORA1 and ATF3 levels may predict response to PD-1 blockade.