Faecalibacterium prausnitzii enzyme reprograms PD-L1 trafficking and sensitizes colorectal cancer to immunotherapy in mice.

Microbiome-host interactions can influence colorectal cancer (CRC) outcomes and the effectiveness of immunotherapy treatment, but the precise mechanisms underlying this are poorly understood. Here we analyse CRC patient cohort data and observe that Facalibacterium prausnitzii abundance in faecal samples correlates with improved CRC survival outcome and immunotherapy response. In vitro assays and experiments in azoxymethane plus dextran sulfate sodium (AOM/DSS) and Apcmin/+ mouse CRC models show that F. prausnitzii extracts have anti-tumour activity. Mass spectrometry identifies F. prausnitzii phosphoribosyl pyrophosphate synthetase (fpPRPS) as a bacterial enzyme that inhibits tumour development and promotes CD8+ T-cell responses. Mechanistically, fpPRPS depletes ATP levels in CRC cells, which then inhibits GTP-GDP exchange on Rab11a, reprogramming CRC energy metabolism. This leads to Rab11a degradation and the disruption of PD-L1 trafficking to reduce the inhibition of T-cell responses. fpPRPS inhibition of tumour progression is PD-L1-dependent. We also show that fpPRPS and anti-PD-1 treatment synergize to promote CD8+ T-cell responses and tumour control in mice. These findings suggest fpPRPS as a potential strategy for sensitizing CRC to immunotherapy.