Title : Dissecting and establishing the gut microbiota plus bile acid–FXR/PD-L1 axis as a promising therapeutic target to enhance immunotherapy in renal cell carcinoma
Abstract:
Objective: To investigate how bile acids—secreted by the liver and metabolized by gut microbiota—affect renal cancer (RCC) progression and to identify potential therapeutic strategies.
Methods: 1.Analyzed clinical data from 1,693 RCC patients in the UK Biobank and 511 RCC patients with liver dysfunction from Wuhan Union Hospital; 2.Integrated transcriptomic data from TCGA and six paired RCC samples; 3.Combined metabolomics of 100 RCC cases (51 controls) with targeted bile acid profiling from 10 paired samples; 4.Analyzed gut microbiota from 51 RCC patients (40 healthy controls) and six immunotherapy mouse models; 5.Conducted biomedical and biochemical experiments for mechanistic validation.
Results: 1.As evidenced before, liver dysfunction is linked to worse RCC prognosis; 2.Bile acid metabolism genes are enriched in RCC; 3.CDCA is elevated in RCC tissues; 4.CDCA activates FXR, upregulating PD-L1 and promoting immune evasion; 5.Ruminococcus gnavus, which metabolizes CDCA, is reduced in RCC and poorly responsive mice; 6.Co-administration of R. gnavus and the FXR inhibitor UDCA enhances RCC immunotherapy efficacy.
Conclusion: Loss of R. gnavus leads to CDCA accumulation in RCC, activating FXR and PD-L1 expression. Supplementing R. gnavus and UDCA improves immunotherapy, suggesting a novel treatment strategy.
