Next-generation probiotics Alistipes onderdonkii enhances the efficacy of anti-PD-1 therapy in colorectal cancer

Abstract

Despite significant breakthroughs of therapeutic antibodies targeting PD-1 in cancer treatment, most colorectal cancer (CRC) patients respond poorly to anti-PD-1 immunotherapy. The combination therapy strategies are used to overcome the limitations mentioned above. Alistipes (A.) onderdonkii has anti-cancer effects. This study aimed to examine A. onderdonkii's effects and the related mechanisms in the anti-PD-1 treatment for CRC. In this study, anti-PD-1 therapy notably affected gut microbiota community composition in mice, particularly upregulating A. onderdonkii abundance. A. onderdonkii supplementation markedly promoted anti-PD-1 therapy's effectiveness on CRC treatment, as manifested by the elevated CD8⁺ T cell infiltration, promoted intestinal barrier integrity, and affected serum metabolomics. A. onderdonkii showed similar effects to the identified next-generation probiotics (NGP) Akkermansia (A.) muciniphila. Additionally, the combination therapy of anti-PD-1 and probiotics supplementation reduced PD-1 level and elevated IL-2 level, indicating that anti-PD-1 combined with A. onderdonkii efficiently restored T cell functions by inhibiting suppressive checkpoints. In conclusion, anti-PD-1 plus A. onderdonkii supplementation could account for a potential method for CRC therapy. These results provide strong evidence for A. onderdonkii as a potential NGP.