{
  "abstract": "Background Adoptive cell therapies (ACTs) are breakthrough cancer treatments centered around CD8 T cell cytotoxicity. Despite much success in hematological cancers, ACT efficacy is limited in solid tumors due to poor tumor infiltration and immunosuppressive tumor microenvironments. Strategies that enhance CD8 T cell antitumor, or Tc1, function are critically needed to extend the benefits of these therapies to more patients.The microbiota is a key factor in dictating responses to various immunotherapies, including ACTs. However, the specific microbial metabolites that enhance CD8 T cell immunity and the mechanisms they employ are understudied. Emerging studies highlight the immune-activating potential of microbial tryptophan catabolites (MTCs), but little is known about their effects on antitumor immunity, especially on CD8 T cells.Methods We tested the ability of MTCs to suppress subcutaneously injected B16F10 tumors, activate Nrf2 and AhR luciferase reporter cell lines, and enhance Tc1 immunity in vitro. Additionally, we pre-treated donor tumor-antigen specific CD8 T cells to determine if MTCs can enhance the efficacy of adoptive transfer in a pmel-1/gp100 model.Results We screened all 13 known MTCs to evaluate their effectiveness in reducing tumor growth. Only tryptamine (Trp), indole-3-aldehyde (I3A), indole-3-proprionic acid (IPA), indole-3-acetic acid (IAA), indole-3-lactic acid (ILA), and indole-3-acrylic acid (IA) suppressed B16F10 tumor growth when intratumorally administered. Trp, I3A, IPA, and IA directly promoted Tc1 cell differentiation during co-culture with CD8 T cells. Additionally, Trp and I3A synergistically enhanced Tc1 effector function, suggesting that MTCs can leverage alternative but complementary pathways, such as aryl hyrdrocarbon receptor (AhR) and nuclear factor erythroid 2-related factor 2 (Nrf2) signaling, to boost CD8 T cell effector function. Most MTCs, with the exception of indole, were able to activate both AhR and Nrf2. Finally, preliminary evidence suggests that ex vivo MTC pre-treatment of tumor antigen specific CD8 T cells promotes a better antitumor response when adoptively transferred into tumor bearing mice.Conclusions Our study provides preliminary evidence that MTCs can impact Tc1 immunity directly in a cell-intrinsic manner and suggests that AhR and Nrf2 are potential checkpoints of MTC-mediated Tc1 enhancement. However, future studies are necessary to fully interrogate the epigenetic, transcriptional, and functional changes incurred to CD8 T cells upon treatment with MTCs, as well as to determine the importance of AhR and/or Nrf2 activation for MTC Tc1 enhancement. Ultimately, we hope that MTCs may be used to bolster CD8 T cell function during ACT ex vivo expansion, allowing for the enhancement of existing cellular therapies.",
  "authors": [
    {
      "affiliations": [
        "University of Pittsburgh School of Medicine, Pittsburgh, PA, USA"
      ],
      "name": "Amanda H Lee"
    },
    {
      "affiliations": [
        "University of Pittsburgh School of Medicine, Pittsburgh, PA, USA"
      ],
      "name": "Surya P Pandey"
    },
    {
      "affiliations": [
        "University of Pittsburgh School of Medicine, Pittsburgh, PA, USA"
      ],
      "name": "Colin R Laughlin"
    },
    {
      "affiliations": [
        "University of Pittsburgh School of Medicine, Pittsburgh, PA, USA",
        "University of Pittsburgh School of Public Heath, Pittsburgh, PA, USA"
      ],
      "name": "Alex C McPherson"
    },
    {
      "affiliations": [
        "University of Pittsburgh School of Medicine, Pittsburgh, PA, USA",
        "UPMC Hillman Cancer Center, Pittsburgh, PA, USA"
      ],
      "name": "Marlies Meisel"
    }
  ],
  "title": "1138 Enhancement of CD8 T cell function with microbial tryptophan catabolites to boost cellular therapy efficacy in solid tumors",
  "uid": "dd4688ab-c20a-5ee3-8423-f8a9f6e94481"
}