Enhancing immunotherapy efficacy in NSCLC through the combined use of phenelzine and to regulate gut microbial metabolite 5-HIAA.

Background: Improving the efficacy of anti-programmed death 1 (PD-1) monoclonal antibody (mAb) therapy remains a major challenge for cancer immunotherapy in non-small cell lung cancer (NSCLC). Gut microbial metabolites can influence immunotherapy efficacy.

Methods: ELISA was used to compare the serum 5-hydroxyindoleacetic acid (5-HIAA) level in patients with NSCLC. Humanized mice were constructed to observe the effect of 5-HIAA on immunotherapy. RNA-seq and flow cytometry were used to analyze the effect of 5-HIAA on tumor-infiltrating lymphocytes. The effects of phenelzine (Phe) and () on 5-HIAA synthesis, antitumor immunity and immunotherapy efficacy were analyzed. Finally, the synergistic effect of Phe combined with on anti-PD-1 mAb was observed.

Results: Here we found that 5-HIAA, which is regulated by gut microbiota, has increased concentrations in the serum of non-responders to immunotherapy. Supplementation of 5-HIAA inhibited the efficacy of anti-PD-1 mAb and tumor infiltration of CD8 T cells. The use of monoamine oxidase inhibitor (MAO-I) Phe inhibited the synthesis of 5-HIAA, then improved the efficacy of anti-PD-1 mAb. In addition, supplementation of can also decrease 5-HIAA in serum. Finally, the combination of Phe and maximally inhibited 5-HIAA synthesis and improved immunotherapy efficacy.

Conclusions: Our investigations reveal that alterations in gut microbial composition leading to increased 5-HIAA synthesis can negatively impact CD8 T cell functionality and the success of immunotherapy. The combination of Phe and supplementation holds potential for optimizing immunotherapy efficacy.