In situ modulation of the gut microbiome with inulin gel for improving cancer immunotherapy

Despite their success, immune checkpoint blockers (ICB) benefit only a subset of patients and pose potential risk of serious immune-related adverse events, underscoring the critical need for new strategies to induce T cell immunity with minimal toxicity. Human microbiome has emerged as the next frontier in drug development, and the gut microbiota has been implicated in patient outcomes following cancer immunotherapy. However, it remains to be seen how to manipulate the gut commensal microbes to achieve systemic anti-tumor immunity. Here, we report that inulin, a widely-consumed dietary fiber, engineered into a colon-retentive oral gel effectively modulated the gut microbiome in situ and induced systemic memory T cell responses, amplifying anti-tumor efficacy of anti-PD-1 ICB in multiple murine tumor models. Oral inulin gel treatments increased the relative abundances of key commensal microbes and their short-chain fatty acids (SCFAs) as metabolites, leading to enhanced memory recall response for IFN-gamma+CD8+ T cells and establishment of stem-like Tcf1+PD-1+CD8+ T cells within the tumor microenvironment. Our dietary fiber-based approach may offer a general strategy for targeting the gut microbiota and addressing dysregulated gut microbiome in the setting of cancer and other pathologies.