Microbiota-Induced IFN-I Signaling Promotes an Antitumor Microenvironment

The tumor microenvironment (TME) is a critical contributor to cancer progression and response to treatment. A critical component of the TME is immune cells, with factors within the TME contributing to a more immunosuppressive phenotype. Mononuclear phagocytes (MP) are key immune cells present in the TME and include monocytes, macrophages, and dendritic cells (DC). These cells can have opposing dual roles in the TME including promoting immunosuppression or stimulating an antitumor response, which has led to the desire to target these cells to skew outcomes toward anticancer immunity. The regulation of the composition and functional state of these cell types, however, still remains to be fully understood. Furthermore, recent literature demonstrates a link between the gut microbiota, antitumor immunity, and response to immunotherapy, but the effect that the microbiota has on the MP population has not been fully appreciated. Lam, Araya, and colleagues used a combination of single-cell sequencing, microbiota perturbation, and functional cell characterization and found that signals from the microbiota program MP in the TME into immunostimulatory monocytes and DCs. Conversely, absence of microbiota skews MP toward tumor-promoting macrophages. Mechanistically, microbiota-released STING agonists, such as c-di-AMP, induce a type I IFN (IFN-I) response in intratumoral monocytes, and the subsequent recruitment and activation of natural killer cells and DCs contributing to the antitumor response. Dietary intervention to manipulate the microbiota composition showed that a high-fiber diet triggers this mechanism through enrichment of the bacterial species Akkermansia muciniphila, and improves the efficacy of immune checkpoint blockade (ICB). When fecal transplants were conducted from ICB responder or non-responder patients with melanoma, a reshaping of the MP landscape within the TME occurred through IFN-I, further pointing to the translational relevance of the findings. The identification of a mechanism by which the microbiota regulates innate immune cells suggests ways in which specific microbiota components can be harnessed to overcome an immunosuppressive TME and improve immunotherapy response.

Lam KC, Araya RE, Huang A, Chen Q, Di Modica M, Rodrigues RR, et al. Microbiota triggers STING-type I IFN-dependent monocyte reprogramming of the tumor microenvironment. Cell 2021;184:5338–56.

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