肿瘤驻留益生菌丁酸梭菌通过抑制 IL-6 介导的免疫抑制改善结直肠癌模型中的 aPD-1 疗效

Most colorectal cancer (CRC) patients do not respond to immune checkpoint blockade (ICB) therapy.

Here, we identify Clostridium butyricum as a probiotic that boosts anti-PD-1 efficacy in CRC. In orthotopic allografts of microsatellite instability-high (MSI-H) and microsatellite stable (MSS) CRC, C. butyricum potentiates tumor suppressive effect of anti-PD-1, which is verified in AOM/DSS-induced CRC and germ-free mice. Single-cell RNA-seq reveals that C. butyricum activates cytotoxic CD8 + T lymphocytes (CTLs) and impairs tumor-associated macrophages (TAMs), especially in conjunction with anti-PD-1.

Mechanistically, C. butyricum surface protein secD binds to CRC cell receptor glucose-regulated protein 78 (GRP78), which inactivates GRP78 and PI3K-AKT-NF-κB pathway, leading to reduced secretion of interleukin (IL)-6, an immunosuppressive cytokine that blunts CTLs and induces TAMs. Translational impact of C. butyricum in boosting anti-PD-1 efficacy is validated in huCD34 + humanized mice and autologous patient-derived CRC organoids-CTLs co-culture system. To summarize, C. butyricum is a promising adjuvant to augment ICB therapy.