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CANCER IMMUNOLOGY

Microbiota shape tumor immunity

Nature Immunology volume 22, page 1469 (2021)Cite this article

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Cell 184, 5338–5356 (2021)

Fairly extensive data now suggest that the microbiota can influence cancer immunity in both positive and negative ways; however, the mechanisms that underlie these effects have remained elusive. In Cell, Goldszmid and colleagues describe an axis stemming from the gut microbiota that supports anti-tumor responses. Using a variety of different mouse tumor models including implantable, genetic and orthotopic approaches, the authors find that compared with normally-housed specific pathogen-free mice, there is impaired tumor control in both germ-free or broad-spectrum antibiotic-treated mice. Germ-free or antibiotic-treated mice show a reshaped tumor microenvironment (TME) in which the monocytes, macrophages and dendritic cells skew towards a pro-tumorgenic profile. Interestingly, these pro-tumor alterations in immune signatures are detectable specifically in the TME but not systemically, for example in the spleen. Systems analysis reveals that there is a reduced type I interferon (IFN-I) signature in the TME and that blockade or the absence of IFN-I receptor signalling in specific pathogen-free mice largely recapitulates the pro-tumor immune signature of germ-free mice. High-fiber diets are known to be protective against various malignancies in both human and mouse models, and the authors observe a similar phenomenon. Using metagenomics of mice maintained on a high-fiber diet, the authors find alterations in gut microbial diversity and in particular an increase in the genus Akkermansia. Monocolonization of germ-free mice with Akkermansia restores an anti-tumor immune profile in the TME and synergizes with the immune checkpoint blockade (ICB) monoclonal antibodies anti-PD-1 and anti-PD-L1 in the control of implanted tumors. Akkermansia is shown to be a rich source of STING receptor agonists, in particular c-di-AMP, which is able to potently stimulate IFN-I responses by monocytes. Similarly, fecal microbiotal transplants from patients responsive to ICB also foster a protective immune signature in germ-free mice. Finally, using published datasets, the authors find that ICB-responsive patients show similar enhancements in mononuclear phagocyte signatures and IFN-I. This pre-clinical study provides extensive mechanistic details into how the microbiota can influence tumor immunity and suggests that dietary manipulations could have beneficial effects in cancer treatment.

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  1. Nature Immunology https://www.nature.com/natimmunol

    Zoltan Fehervari

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  1. Zoltan Fehervari
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Correspondence to Zoltan Fehervari.

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Fehervari, Z. Microbiota shape tumor immunity. Nat Immunol 22, 1469 (2021). https://doi.org/10.1038/s41590-021-01082-1

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