{
  "abstract": "Background Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, yet response rates remain variable, with the gut microbiome emerging as a key modulator of efficacy. Prebiotic interventions represent a promising strategy to beneficially shape the microbiota. Lactulose, a non-absorbable prebiotic, has been shown to promote gut health and increase the abundance of beneficial bacteria such as Bifidobacterium,1 a taxon known to be associated with enhanced anti-tumor immune responses.2 However, the role of lactulose in anti-tumor response and its impact on the efficacy of ICIs remains unknown.Methods The anti-tumor effects of lactulose were evaluated in C57BL/6 mice bearing B16.SIY melanoma or MC38 colorectal cancer models, both as a monotherapy and in combination with anti-PD-L1 blockade. Body weight, activity, tumor growth and survival were monitored. Mechanistic investigations involved CD8 + T cell depletion studies, and comprehensive immune profiling of the tumor microenvironment (TME) and lymphoid organs using flow cytometry and single-cell RNA sequencing. Microbial and metabolic changes were mapped by 16S rRNA sequencing, shotgun metagenomics, and untargeted metabolomics. Microbiota causality was tested by broad-spectrum antibiotic depletion and fecal microbiota transplantation (FMT) experiments.Results We found that prophylactic lactulose supplementation significantly inhibited tumor growth as a single agent and robustly enhanced the efficacy of anti-PD-L1 therapy. This anti-tumor effect was completely abrogated upon depletion of CD8 + T cells and antibiotic treatment, demonstrating a critical dependence on the host immune system and the gut microbiota. Consistent with this, lactulose treatment led to a significant increase of total and tumor antigen-specific (SIY+) CD8+ T cells in the TME. Microbiome analysis identified a marked expansion of Bifidobacterium, particularly Bifidobacterium pseudolongum. Notably, a therapeutic strain of B. pseudolongum isolated from lactulose-treated mice was sufficient to recapitulate the anti-tumor effect when administered alone. Mechanistically, these effects were associated with systemic increase in microbial-derived metabolites implicated in anti-tumor immunity, including inosine3 and the tryptophan metabolite indole-3-lactic acid (ILA).4 Conclusions Lactulose rewires gut microbial and metabolic profiles to bolster CD8 + T cell-mediated tumor control and potentiate anti-PD-L1 efficacy. Accordingly, lactulose warrants prospective evaluation as a prebiotic adjuvant to enhance immunotherapy outcomes.References Odenwald, Matthew A, et al. Bifidobacteria metabolize lactulose to optimize gut metabolites and prevent systemic infection in patients with liver disease. Nature Microbiology 2023;8(11):2033–2049.Sivan, Ayelet, et al. Commensal bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science 2015;350(6264):1084–1089.Mager, Lukas F, et al. Microbiome-derived inosine modulates response to checkpoint inhibitor immunotherapy. Science 2020;369(6510):1481–1489.Zhang, Qingqing, et al. Lactobacillus plantarum-derived indole-3-lactic acid ameliorates colorectal tumorigenesis via epigenetic regulation of CD8+ T cell immunity. Cell Metabolism 2023;35(6):943–960.",
  "authors": [
    {
      "affiliations": [
        "University of Chicago, Chicago, IL, USA"
      ],
      "name": "Yaopeng Li"
    },
    {
      "affiliations": [
        "University of Chicago, Chicago, IL, USA"
      ],
      "name": "Vyara Matson"
    },
    {
      "affiliations": [
        "University of Chicago, Chicago, IL, USA"
      ],
      "name": "Thomas F Gajewski"
    }
  ],
  "title": "423 Lactulose modulates the gut microbiota to potentiate anti-tumor immunity and enhance anti-PD-L1 efficacy",
  "uid": "84bb7182-c637-5242-acc7-56cc285753e3"
}