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Updated: Jun 26, 2025
Isolation and Characterization of Dendritic Cells and Macrophages from the Mouse Intestine
Published on: May 21, 2012
TREM2 deficiency reprograms intestinal macrophages and microbiota to enhance anti-PD-1 tumor immunotherapy
Blanda Di Luccia1,2, Martina Molgora1, Darya Khantakova1
1Department of Pathology and Immunology, Washington University School of Medicine in Saint Louis, St. Louis, MO 63110, USA.
Abstract:
The gut microbiota and tumor-associated macrophages (TAMs) affect tumor responses to anti-programmed cell death protein 1 (PD-1) immune checkpoint blockade. Reprogramming TAM by either blocking or deleting the macrophage receptor triggering receptor on myeloid cells 2 (TREM2) attenuates tumor growth, and lack of functional TREM2 enhances tumor elimination by anti-PD-1. Here, we found that anti-PD-1 treatment combined with TREM2 deficiency in mice induces proinflammatory programs in intestinal macrophages and a concomitant expansion of Ruminococcus gnavus in the gut microbiota. Gavage of wild-type mice with R. gnavus enhanced anti-PD-1-mediated tumor elimination, recapitulating the effect occurring in the absence of TREM2. A proinflammatory intestinal environment coincided with expansion, increased circulation, and migration of TNF-producing CD4+ T cells to the tumor bed. Thus, TREM2 remotely controls anti-PD-1 immune checkpoint blockade through modulation of the intestinal immune environment and microbiota, with R. gnavus emerging as a potential probiotic agent for increasing responsiveness to anti-PD-1.
Insights
Mice lacking the macrophage receptor TREM2 showed enhanced anti-PD-1 tumor elimination. This was linked to gut bacteria Ruminococcus gnavus, suggesting it could be a probiotic to boost anti-PD-1 therapy effectiveness.
Area of Science:
- Immunology
- Microbiology
- Oncology
Background:
- Tumor-associated macrophages (TAMs) and gut microbiota influence anti-programmed cell death protein 1 (PD-1) therapy.
- Modulating the macrophage receptor TREM2 impacts tumor growth and anti-PD-1 response.
Purpose of the Study:
- To investigate the role of TREM2 deficiency in anti-PD-1 therapy response.
- To explore the interplay between TREM2, gut microbiota, and intestinal immunity in anti-PD-1 blockade.
Main Methods:
- Utilized a mouse model with TREM2 deficiency and anti-PD-1 treatment.
- Analyzed changes in intestinal macrophages and gut microbiota composition.
- Administered Ruminococcus gnavus via gavage to wild-type mice.
Main Results:
- TREM2 deficiency combined with anti-PD-1 induced proinflammatory programs in intestinal macrophages.
- A significant expansion of Ruminococcus gnavus was observed in the gut microbiota.
- Gavage with R. gnavus enhanced anti-PD-1-mediated tumor elimination, mimicking TREM2 deficiency effects.
- Observed a proinflammatory intestinal environment with increased TNF-producing CD4+ T cells migrating to tumors.
Conclusions:
- TREM2 deficiency remotely enhances anti-PD-1 therapy by modulating the intestinal immune environment and microbiota.
- Ruminococcus gnavus plays a key role in this enhanced response.
- R. gnavus is a potential probiotic agent to improve anti-PD-1 therapy responsiveness.
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