Landscape of tumoral ecosystem for enhanced anti-PD-1 immunotherapy by gut Akkermansia muciniphila.

Publication Title

Cell Rep

Document Type

Article

Publication Date

6-25-2024

Keywords

oregon; chiles; Animals; Mice; Akkermansia; B7-H1 Antigen; CD8-Positive T-Lymphocytes; Gastrointestinal Microbiome; Immune Checkpoint Inhibitors; Immunotherapy; Mice, Inbred C57BL; Neutrophils; Programmed Cell Death 1 Receptor; Receptors, CXCR3; Tumor Microenvironment; Neoplasms

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.

Clinical Institute

Cancer

Clinical Institute

Digestive Health

Specialty

Oncology

Specialty

Nephrology

Specialty

Gastroenterology

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