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  • IDDF2024-ABS-0178 Acetate-producing bifidobacterium catenulatum boosts anti-PD1 efficacy in colorectal cancer via activation of cytotoxic CD8+ cells

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Basic Gastroenterology
IDDF2024-ABS-0178 Acetate-producing bifidobacterium catenulatum boosts anti-PD1 efficacy in colorectal cancer via activation of cytotoxic CD8+ cells
  1. Xiang Li1,
  2. Mingxu Xie2,
  3. Xing Kang2,
  4. Yue Chen3,
  5. Yinnan Chen3,
  6. Jing Han3,
  7. Kai Li1,
  8. Junjun She3,
  9. Jun Yu2
  1. 1Department of Otorhinolaryngology-Head and Neck Surgery, First Affiliated Hospital of Xi’an Jiaotong University, China
  2. 2Institute of Digestive Disease and The Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong
  3. 3Center for Gut Microbiome Research, Med-X Institute Centre, First Affiliated Hospital of Xi’an Jiaotong University, China

Abstract

Background Bifidobacterium catenulatum was reported to attenuate inflammation through modulating gut microbiota. Here, we investigated the roles of B. catenulatum as a potential probiotic in suppressing tumorigenesis and improving the efficacy of immune checkpoint blockade (ICB) in colorectal cancer (CRC).

Methods B. catenulatum abundance was evaluated in CRC patients (n=308) and healthy subjects (n=288) based on shotgun metagenomic sequencing from multiple cohorts. The effect of B. catenulatum in CRC tumorigenesis was determined in mice induced by azoxymethane (AOM)/dextran sulfate sodium (DSS) injection. The effect of B. catenulatum on anti-PD1 therapeutic efficacy was evaluated in CT26 (MSI-low) and MC38 (MSI-high) syngeneic mouse models. The changes in immune landscapes were identified by multicolor flow cytometry and immunohistochemistry staining. Functional metabolites were identified by non-targeted and targeted metabolomics assays (GC-MS) and verified in human CRC cell lines. The effect of B. catenulatum and its metabolite on anti-PD1 efficacy was assessed in Apcmin/+ mice and AOM/DSS-induced tumorigenesis mice.

Results B. catenulatum was significantly depleted in stool samples of CRC patients compared to healthy controls (p<0.05). Oral administration of B. catenulatum significantly inhibited AOM/DSS-induced CRC tumorigenesis in mice. B. catenulatum boosted anti-PD-1 therapy in CT26, but not MC38 allografts. Acetate was identified as an enriched metabolite of B. catenulatum by metabolomic profiling of bacteria culture supernatants and stool samples from B. catenulatum-treated mice. We confirmed that B. catenulatum and its derived acetate significantly augmented anti-PD1 efficacy and increased the intratumoral infiltration of cytotoxic CD8+ T cells in Apcmin/+ mice. Mechanistically, acetate directly binds to monocarboxy-late transporter (MCT)-4 in CD8+ T cells and activates its downstream mitogen-activated protein kinases (MAPK) signaling. Pharmacological blockade of MCT-4 by VB124 significantly abolished the activation of CD8+ T cells by acetate in vitro.

Conclusions B. catenulatum protects against CRC tumorigenesis. B. catenulatum generated acetate boosts anti-PD1 efficacy in MSI-low CRC. Live B. catenulatum is a potential probiotic for CRC prevention and adjuvant immunotherapy.

https://doi.org/10.1136/gutjnl-2024-IDDF.79

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