Landscape of tumoral ecosystem for enhanced anti-PD-1 immunotherapy by gut Akkermansia muciniphila
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Updated: Jun 25, 2025
Multiplexed Immunofluorescence Analysis and Quantification of Intratumoral PD-1+ Tim-3+ CD8+ T Cells
Published on: February 8, 2018
Zhuxian Zhu1, Jianguo Huang2, Yanling Zhang3
1Department of Nephrology, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China.
Abstract:
Gut Akkermansia muciniphila (Akk) has been implicated in impacting immunotherapy or oncogenesis. This study aims to dissect the Akk-associated tumor immune ecosystem (TIME) by single-cell profiling coupled with T cell receptor (TCR) sequencing. We adopted mouse cancer models under anti-PD-1 immunotherapy, combined with oral administration of three forms of Akk, including live Akk, pasteurized Akk (Akk-past), or its membrane protein Amuc_1100 (Amuc). We show that live Akk is most effective in activation of CD8 T cells by rescuing the exhausted type into cytotoxic subpopulations. Remarkably, only live Akk activates MHC-II-pDC pathways, downregulates CXCL3 in Bgn(+)Dcn(+) cancer-associated fibroblasts (CAFs), blunts crosstalk between Bgn(+)Dcn(+) CAFs and PD-L1(+) neutrophils by a CXCL3-PD-L1 axis, and further suppresses the crosstalk between PD-L1(+) neutrophils and CD8 T cells, leading to the rescue of exhausted CD8 T cells. Together, this comprehensive picture of the tumor ecosystem provides deeper insights into immune mechanisms associated with gut Akk-dependent anti-PD-1 immunotherapy.
Insights
Live Akkermansia muciniphila (Akk) enhances anti-PD-1 immunotherapy by activating CD8 T cells and modulating the tumor immune microenvironment. It rescues exhausted T cells and suppresses suppressive cell interactions, improving cancer treatment outcomes.
Area of Science:
- Immunology
- Microbiome research
- Cancer biology
Background:
- Gut Akkermansia muciniphila (Akk) influences immunotherapy and cancer development.
- Understanding the tumor immune ecosystem (TIME) is crucial for effective cancer treatment.
Purpose of the Study:
- To dissect the Akk-associated tumor immune ecosystem (TIME) using advanced single-cell and TCR sequencing techniques.
- To investigate the impact of different Akk formulations (live, pasteurized, membrane protein) on anti-PD-1 immunotherapy in mouse cancer models.
Main Methods:
- Utilized mouse cancer models undergoing anti-PD-1 immunotherapy.
- Administered oral live Akk, pasteurized Akk (Akk-past), or its membrane protein Amuc_1100 (Amuc).
- Employed single-cell profiling and T cell receptor (TCR) sequencing to analyze TIME composition and function.
Main Results:
- Live Akk demonstrated superior efficacy in activating CD8 T cells, converting exhausted cells into cytotoxic subpopulations.
- Only live Akk activated MHC-II-pDC pathways and downregulated CXCL3 in cancer-associated fibroblasts (CAFs).
- Live Akk disrupted the CXCL3-PD-L1 axis, reducing crosstalk between CAFs, neutrophils, and CD8 T cells, thereby rescuing exhausted CD8 T cells.
Conclusions:
- Live Akkermansia muciniphila significantly enhances anti-PD-1 immunotherapy by orchestrating complex immune interactions within the TIME.
- The study provides a detailed mechanistic understanding of how gut bacteria modulate anti-cancer immunity, highlighting live Akk as a potent therapeutic enhancer.
