Gut Associated Metabolites Enhance PD-L1 Blockade Efficacy in Prostate Cancer.

Abstract

BACKGROUND: The gut microbiome has emerged as a critical modulator of cancer immunotherapy response. However, the mechanisms by which gut-associated metabolites influence checkpoint blockade efficacy in prostate cancer (PC) remain not fully explored. The study aimed to explore how gut metabolites regulate death-ligand 1 (PD-L1) blockade via exosomes and boost immune checkpoint inhibitors (ICIs) in PC. METHODS: We recruited 70 PC patients to set up into five subgroups. The integrated multi-omics analysis was performed. In parallel, we validated the function of gut microbiome-associated metabolites on PD-L1 production and immunotherapy treatment efficacy in PC cell lines and transgenic adenocarcinoma of the mouse prostate (TRAMP) models. RESULTS: We identified two metabolites, 16(R)-Hydroxyeicosatetraenoic acid (16(R)-HETE) and 6-Keto-Prostaglandin E1 (6-Keto-PGE1), that positively correlated with the plasma exosomal PD-L1 levels. Theexperiments found that both 16(R)-HETE and 6-Keto-PGE1 can enhance PD-L1 expression at the mRNA, protein, and exosome levels in both human and mouse PC cell lines, which were also validatedbased on subcutaneous mouse models. Both metabolites significantly promoted the anti-PD-L1 efficacy against PCon a TRAMP mouse model. CONCLUSIONS: Targeting the "gut-tumor metabolic axis" is a promising strategy to improve the efficacy of immune checkpoint inhibitors in tumors.