Objective: Gut microbiota is a key player in dictating immunotherapy response. We aimed to explore the immunomodulatory effect of probiotic and its role in improving anti-programmed cell death protein 1 (PD1) efficacy against colorectal cancer (CRC).
Design: The effects of in anti-PD1 response were assessed in syngeneic mouse models and azoxymethane/dextran sulfate sodium-induced CRC model. The change of immune landscape was identified by multicolour flow cytometry and validated by immunohistochemistry staining and in vitro functional assays. Liquid chromatography-mass spectrometry was performed to identify the functional metabolites.
Results: significantly improved anti-PD1 efficacy in two syngeneic mouse models with different microsatellite instability (MSI) statuses (MSI-high for MC38, MSI-low for CT26). Such effect was confirmed in CRC tumourigenesis model. synergised with anti-PD1 therapy by reducing Foxp3 CD25 regulatory T cell (Treg) intratumoural infiltration, and enhancing effector function of CD8 T cells. -derived indole-3-carboxylic acid (ICA) was identified as the functional metabolite. Mechanistically, ICA inhibited indoleamine 2,3-dioxygenase (IDO1) expression, therefore suppressing kynurenine (Kyn) production in tumours. ICA also competed with Kyn for binding site on aryl hydrocarbon receptor (AHR) and antagonised Kyn binding on CD4 T cells, thereby inhibiting Treg differentiation in vitro. ICA phenocopied effect and significantly improved anti-PD1 efficacy in vivo, which could be reversed by Kyn supplementation.
Conclusion: -derived ICA improved anti-PD1 efficacy in CRC through suppressing CD4+Treg differentiation and enhancing CD8+T cell function by modulating the IDO1/Kyn/AHR axis. is a potential adjuvant to augment anti-PD1 efficacy against CRC.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10715476 | PMC |
| http://dx.doi.org/10.1136/gutjnl-2023-329543 | DOI Listing |
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