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

Cancer Cell. 2020 Mar 16;37(3):324-339.e8. doi: 10.1016/j.ccell.2020.02.006.


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.

Keywords: PD-L1/PD-1; adenosine A1 receptor; adenosine signaling; cAMP-dependent transcription factor 3; combination therapy; immune checkpoint; immunotherapy; melanoma; non-small cell lung cancer; tumor microenvironment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 3 / metabolism*
  • Adenosine A1 Receptor Antagonists / pharmacology*
  • Adenosine A1 Receptor Antagonists / therapeutic use
  • Adult
  • Aged
  • Animals
  • Antineoplastic Agents, Immunological / pharmacology
  • Antineoplastic Combined Chemotherapy Protocols / metabolism
  • B7-H1 Antigen / antagonists & inhibitors
  • B7-H1 Antigen / genetics
  • B7-H1 Antigen / metabolism*
  • Carcinoma, Non-Small-Cell Lung / drug therapy
  • Carcinoma, Non-Small-Cell Lung / immunology
  • Cell Line, Tumor
  • Cytarabine / metabolism
  • Female
  • Humans
  • Lomustine / metabolism
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / immunology
  • Male
  • Melanoma / drug therapy
  • Melanoma / immunology*
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Middle Aged
  • Mitoxantrone / metabolism
  • Prednisone / metabolism
  • Receptor, Adenosine A1 / metabolism*
  • Tumor Escape / drug effects*
  • Xenograft Model Antitumor Assays


  • ATF3 protein, human
  • Activating Transcription Factor 3
  • Adenosine A1 Receptor Antagonists
  • Antineoplastic Agents, Immunological
  • B7-H1 Antigen
  • CD274 protein, human
  • Receptor, Adenosine A1
  • Cytarabine
  • Lomustine
  • Mitoxantrone
  • Prednisone

Supplementary concepts

  • CAMP combination