{
  "abstract": "Background A significant challenge in cancer immunotherapy is the dysfunction of cytotoxic CD8 + T cells within the tumor microenvironment (TME), where immunoinhibitory signals and metabolic constraints drive these cells into an exhausted state. A hallmark of exhausted CD8+ T cells is the accumulation of intracellular reactive oxygen species (ROS), exacerbated by the hypoxic and nutrient-deprived conditions of the TME. We identified the upregulation of ME1 in CD8+ tumor-infiltrating lymphocytes (TILs), which is crucial for T cell responses to immune checkpoint inhibitor (ICI) therapy. ME1 overexpression (OE) in CD8+ TILs prevents the accumulation of excessive ROS and increases granzyme B expression. However the underlying mechanism of action of ME1 has not been clearly defined.Methods To dissect the molecular mechanism that maintain the functional capacity and metabolic fitness of resilient CD8 + T cells through ME1 upregulation, we produced CD8-specific ME1 transgenic mice for T cell metabolism study and therapeutic potential evaluation. For metabolic tracing, [U-¹³C6] glucose was administered in vivo via continuous infusion. CD8+ T cells were subsequently isolated from both spleen and tumor tissues, and aspartate isotopologue distributions were analyzed using mass spectrometry to evaluate metabolic flux through the TCA cycle. Additionally, bulk RNA sequencing was performed on sorted CD8+ T cells—both activated and resting—from ME1-overexpressing and wild-type mice to assess transcriptomic differences associated with ME1 expression. In a separate adoptive transfer experiment, TILs from ME1 transgenic and wild-type mice were expanded in vitro and administered peritumorally into recipient tumor-bearing mice to evaluate their anti-tumor efficacy.Results Using the in vivo [U-¹³C 6] glucose metabolic tracing model, we found that ME1 OE influences TCA cycle substrate availability by altering pyruvate flux through malate-to-pyruvate conversion and other metabolic pathways, collectively contributing to a balanced redox state. At the transcriptional level, ME1 OE elevated the expression of Fasl and Gzmk in activated T cells—key mediators of cytotoxic function. Notably, even in resting CD8+ T cells, ME1 OE induced higher expression of Fasl, Gzmk, and Gzmb. Accordingly, the adoptive transfer of ME1 OE TILs demonstrated strong therapeutic effects in vivo compared to control TILs.Conclusions Collectively, we revealed an undisclosed role of ME1 in CD8 + T cells in maintaining metabolic fitness and cytotoxic function within the TME, proposing ME1 as a new therapeutic target for T cell-based immunotherapy.",
  "authors": [
    {
      "affiliations": [
        "Mayo Clinic, Rochester, MN, USA"
      ],
      "name": "Aubrey Liew"
    }
  ],
  "title": "713 ME1 upregulation promotes metabolic fitness and cytotoxic function of CD8+ tumor-infiltrating lymphocytes",
  "uid": "5b6d0950-d818-529e-8cae-3cb19106c916"
}