The performance of immune-checkpoint inhibitors, which benefit only a subset of patients and can cause serious immune-related adverse events, underscores the need for strategies that induce T-cell immunity with minimal toxicity. The gut microbiota has been implicated in the outcomes of patients following cancer immunotherapy, yet manipulating the gut microbiome to achieve systemic antitumour immunity is challenging. Here we show in multiple murine tumour models that inulin—a widely consumed dietary fibre—formulated as a ‘colon-retentive’ orally administered gel can effectively modulate the gut microbiome in situ, induce systemic memory-T-cell responses and amplify the antitumour activity of the checkpoint inhibitor anti-programmed cell death protein-1 (α-PD-1). Orally delivered inulin-gel treatments increased the relative abundances of key commensal microorganisms and their short-chain-fatty-acid metabolites, and led to enhanced recall responses for interferon-γ+CD8+ T cells as well as to the establishment of stem-like T-cell factor-1+PD-1+CD8+ T cells within the tumour microenvironment. Gels for the in situ modulation of the gut microbiome may be applicable more broadly to treat pathologies associated with a dysregulated gut microbiome.
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The main data supporting the findings of this study are available within the paper and its Supplementary Information. The raw and analysed datasets generated during the study are too large to be publicly shared, but they are available for research purposes from the corresponding author on reasonable request. The bacterial 16S rRNA sequencing data have been deposited in the NCBI Sequence Read Archive (accession number: PRJNA715170).
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This work was supported by the NIH (grant nos R01AI127070, R01EB022563, R01CA210273, U01CA210152, R01DK125087, P30CA046592). J.J.M. is supported by an NSF CAREER Award (grant no. 1553831). D.N. is supported by NCI grant nos R01CA227622, R01CA222251 and R01CA204969; a Rogel Cancer Center grant and a Forbes Scholar Award. We acknowledge the NIH Tetramer Core Facility (contract HHSN272201300006C) for the provision of MHC-I tetramers and C. H. Kim for the provison of GPR43−/− mice. Opinions, interpretations, conclusions and recommendations are those of the author and are not necessarily endorsed by the Department of Defense. We thank M. E. Aikins for critical review of the manuscript, Y. Xu for ELISPOT tests, K. Saud for rheology tests, J. Lu for help with the microbiota data analysis and H. He for helping with the animal studies. Figure 1 was created by the authors using BioRender.com.
A patent application (WO/2021/061789) for in situ modulation of the gut microbiome has been filed, with J.J.M., K.H., J.X. and X. H. as inventors.
Peer review information Nature Biomedical Engineering thanks Bertrand Routy and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Han, K., Nam, J., Xu, J. et al. Generation of systemic antitumour immunity via the in situ modulation of the gut microbiome by an orally administered inulin gel. Nat Biomed Eng (2021). https://doi.org/10.1038/s41551-021-00749-2