{
  "abstract": "Background The tumor micro-environment (TME) is enriched with extracellular ATP, which is rapidly converted to adenosine (ADO) by ectonucleotidases such as CD39 and CD73. Elevated adenosine levels suppress antitumor immunity by activating the A2A receptor (A2aR) signaling axis, leading to impaired function of immune effector cells and immune evasion. Thus, blockade of the adenosine-A2aR pathway represents a promising strategy to overcome resistance to immune checkpoint inhibitors (ICIs), particularly in solid tumors with adenosine-rich TMEs.Methods A potent and selective A2aR antagonist, COMP-015 was evaluated for its ability to block A2aR signaling under high-adenosine conditions. In vitro studies assessed downstream A2aR signaling markers, including intracellular cAMP and phosphorylated CREB (p-CREB), using A2aR-overexpressing cell lines and immune cells respectively, stimulated with adenosine or NECA under TME-like conditions. In vivo antitumor efficacy was investigated in syngeneic tumor models, under adenosine-enriched conditions that mimic the tumor microenvironment, evaluating both monotherapy and combination therapy.Results COMP-015 effectively suppressed intracellular cAMP levels and p-CREB expression under TME-mimicking conditions. In immune cells, NECA treatment led to functional suppression, which was reversed by COMP-015, indicating restoration of immune cell activation under adenosine-rich conditions. In vivo, antitumor efficacy of COMP-015 was observed in combination with an immune checkpoint inhibitor (ICI) in the CT26 tumor model. In additional syngeneic tumor model, COMP-015 demonstrated therapeutic activity both as monotherapy and in combination therapy.Conclusions Selective inhibition of A2aR signaling under adenosine-rich conditions restores immune effector cell function and enhances antitumor immunity. These findings support the therapeutic potential of A2aR antagonism as a novel strategy to overcome immune resistance and improve the efficacy of existing immunotherapies in solid tumors characterized by high adenosine burden.",
  "authors": [
    {
      "affiliations": [
        "CKD Research Institute, Yongin-si, Gyeonggi-do, Republic of Korea"
      ],
      "name": "Su Jung Park"
    },
    {
      "affiliations": [
        "CKD Research Institute, Yongin-si, Gyeonggi-do, Republic of Korea"
      ],
      "name": "Seongmook Kang"
    },
    {
      "affiliations": [
        "CKD Research Institute, Yongin-si, Gyeonggi-do, Republic of Korea"
      ],
      "name": "Seo-Yeon Ko"
    },
    {
      "affiliations": [
        "CKD Research Institute, Yongin-si, Gyeonggi-do, Republic of Korea"
      ],
      "name": "Sung Jun Kang"
    },
    {
      "affiliations": [
        "CKD Research Institute, Yongin-si, Gyeonggi-do, Republic of Korea"
      ],
      "name": "Changsik Lee"
    },
    {
      "affiliations": [
        "CKD Research Institute, Yongin-si, Gyeonggi-do, Republic of Korea"
      ],
      "name": "Ju-Hee Lee"
    }
  ],
  "title": "1262 Selective A2aR antagonism restores antitumor immunity in adenosine-enriched tumor microenvironments",
  "uid": "a62f81ab-b1b8-5621-b895-f86daef0427c"
}