{
  "abstract": "Background Adenosine is an immunosuppressive metabolite that is overproduced in the tumor microenvironment and a major player in tumor-induced immunosuppression. Work from our group has contributed to show that adenosine binding to the Adenosine A2A Receptor (A2AR) suppresses CD8 T cell function and activation in the tumor microenvironment, whereas blocking A2AR restimulates anticancer CD8 T cell responses. 1–3 In this study, I aimed to identify novel therapeutics that can block A2AR signaling, thus restoring CD8 T cell anticancer function.Methods Using molecular docking modeling, I have found that the nucleoside analog forodesine binds to A2AR with a similar ∆G and similar binding residues as adenosine. I tested forodesine in primary CD8 T-cells against an adenosine agonist and measured functional markers associated with T-cell activation and A2AR signaling using flow cytometry. I also did in vivo studies on immunocompetent mice to see the immunomodulatory effects of forodesine.Results I found that forodesine rescues CD8 T-cell activation by binding to A2AR and counteracting adenosine-mediated immunosuppression. I also tested forodesine in highly immunosuppressive Triple-Negative Breast Cancer (TNBC) mouse models and found that forodesine reduces tumor growth via stimulation of CD8 T-cell responses.Conclusions Based on our findings, nucleoside analogs, like forodesine, could be investigated as novel Immunotherapeutics to successfully stimulate T-cell responses against cancer.Acknowledgements Giulia Monticone, Ph.D., my mentor Zhi Huang, Ph.D. Kristina Larter Lucio Miele M.D., Ph.D., PI Laura Naldi LSU HSC Honors ProgramReferences Monticone G, Huang Z, Hewins P, Cook T, Mirzalieva O, King B, Larter K, Miller-Ensminger T, Sanchez-Pino MD, Foster TP, Nichols OV, Ramsay AJ, Majumder S, Wyczechowska D, Tauzier D, Gravois E, Crabtree JS, Garai J, Li L, Zabaleta J, Miele L. Novel immunomodulatory properties of adenosine analogs promote their antiviral activity against SARS-CoV-2. EMBO Reports. 2024;25(8):3547–3573. https://doi.org/10.1038/s44319-024-00189-4Monticone G, Huang Z, Csibi F, Leit S, Ciccone D, Champhekar AS, Austin JE, Ucar DA, Hossain F, Ibba SV, Boulares AH, Carpino N, Xu K, Majumder S, Osborne BA, Loh C, Miele L. Targeting the Cbl-b-Notch1 axis as a novel immunotherapeutic strategy to boost CD8+ T-cell responses. Front Immunol. 2022 Aug 26;13:987298. doi: 10.3389/fimmu.2022.987298. PMID: 36090975; PMCID: PMC9459147.King B, Huang Z, Hewins P, Cook T, Mirzalieva O, Larter K, Wyczechowska D, Crabtree J, Garai J, Li L, Zabaleta J, Barbier M, Del Valle L, Jurado K, Miele L, Monticone G. Adenosine analogs have immunomodulatory antiviral properties through the adenosine A2A receptor pathway. J Immunol .1 May 2024;212(1_Supplement):1299–4492.",
  "authors": [
    {
      "affiliations": [
        "Louisiana State University Health Sciences Center New Orleans School of Medicine, New Orleans, LA, USA"
      ],
      "name": "Brionna King"
    },
    {
      "affiliations": [
        "Louisiana State University Health Sciences Center New Orleans School of Medicine, New Orleans, LA, USA"
      ],
      "name": "Zhi Huang"
    },
    {
      "affiliations": [
        "Louisiana State University Health Sciences Center New Orleans School of Medicine, New Orleans, LA, USA"
      ],
      "name": "Giulia Monticone"
    }
  ],
  "title": "1177 Forodesine has anticancer immunomodulatory properties through the adenosine pathway",
  "uid": "beb5c451-fd9d-5806-a2d8-32eb08a722d4"
}