Details

Autor(en) / Beteiligte

• Lam, Khiem C.
• Araya, Romina E.
• Huang, April
• Chen, Quanyi
• Di Modica, Martina
• Rodrigues, Richard R.
• Lopès, Amélie
• Johnson, Sarah B.
• Schwarz, Benjamin
• Bohrnsen, Eric
• Cogdill, Alexandria P.
• Bosio, Catharine M.
• Wargo, Jennifer A.
• Lee, Maxwell P.
• Goldszmid, Romina S.

Titel

Microbiota triggers STING-type I IFN-dependent monocyte reprogramming of the tumor microenvironment

Ist Teil von

• Cell, 2021-10, Vol.184 (21), p.5338-5356.e21

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2021

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• The tumor microenvironment (TME) influences cancer progression and therapy response. Therefore, understanding what regulates the TME immune compartment is vital. Here we show that microbiota signals program mononuclear phagocytes in the TME toward immunostimulatory monocytes and dendritic cells (DCs). Single-cell RNA sequencing revealed that absence of microbiota skews the TME toward pro-tumorigenic macrophages. Mechanistically, we show that microbiota-derived stimulator of interferon genes (STING) agonists induce type I interferon (IFN-I) production by intratumoral monocytes to regulate macrophage polarization and natural killer (NK) cell-DC crosstalk. Microbiota modulation with a high-fiber diet triggered the intratumoral IFN-I-NK cell-DC axis and improved the efficacy of immune checkpoint blockade (ICB). We validated our findings in individuals with melanoma treated with ICB and showed that the predicted intratumoral IFN-I and immune compositional differences between responder and non-responder individuals can be transferred by fecal microbiota transplantation. Our study uncovers a mechanistic link between the microbiota and the innate TME that can be harnessed to improve cancer therapies. [Display omitted] •Microbiota-induced type I IFN programs antitumorigenic mononuclear phagocytes (MPs)•Monocytes in the TME produce type I IFN in response to microbial STING agonists•High-fiber diet induces type I IFN, remodels MPs in the TME, and improves ICB efficacy•Microbiota from ICB responders induces IFN-I and shapes the MP landscape in the TME The gut microbiota tunes the pro/anti-tumorigenic balance of the tumor microenvironment via a STING-type I IFN-dependent mechanism. Feeding a high-fiber diet or transferring the fecal microbiota from immune checkpoint blockade (ICB) responder melanoma individuals triggers this pathway and programs intratumoral mononuclear phagocytes to promote anticancer immunity and ICB efficacy.