TREM2 Deficiency Reprograms Intestinal Macrophages and Microbiota to Enhance Anti–PD-1 Tumor Immunotherapy

TREM2 Deficiency Remodels Intestinal Macrophages and Microbiota to Enhance Anti-PD-1 Tumor Immunotherapy

A research team from the Washington University School of Medicine, led by Blanda Di Luccia and other scientists, recently published a study in the journal Science Immunology, revealing how intestinal microbiota and tumor-associated macrophages influence anti-PD-1 immune checkpoint blockade therapy. The study confirmed that blocking or deleting the triggering receptor TREM2 on macrophages can enhance the anti-tumor T cell response and demonstrated that TREM2-deficient mice exhibit a transition of intestinal macrophages to a pro-inflammatory state and an expansion of the gut microbiota Ruminococcus gnavus after anti-PD-1 treatment.

Research Background

Immune checkpoint inhibitors (CPIs) that block proteins such as PD-1, PD-L1, and CTLA-4 have achieved success in treating various cancers; however, a considerable number of patients do not sustain responses or relapse. To improve the efficacy of CPIs, researchers began exploring adjuvant therapeutic strategies. Concurrently, the role of gut microbiota in tumor immunotherapy has gradually gained attention.

Research Findings

The study found that the deletion of TREM2 led to a pro-inflammatory shift in intestinal macrophages in mice, accompanied by an expansion of the gut microbiota Ruminococcus gnavus. Compared to wild-type mice, TREM2-deficient mice exhibited stronger tumor control following anti-PD-1 therapy. This effect could be replicated by orally administering Ruminococcus gnavus to wild-type mice, indicating that R.gnavus may serve as a potential probiotic to enhance the responsiveness to anti-PD-1 therapy. Cytokine analysis showed that consistent with the pro-inflammatory gut environment, TREM2-deficient mice had a higher number of TNFα-producing CD4+ T cells, which might migrate to the tumor area, thereby improving tumor growth control.

Research Significance

This study deepens our understanding of how the gut microbiota and host immune environment jointly regulate the response to tumor immunotherapy. Specifically, it suggests the potential of modulating specific bacterial strains as an adjuvant therapeutic strategy, providing theoretical support for clinical trials.

Research Methods and Procedures

The research team conducted control experiments by inoculating MCA/1956 sarcoma cells in both wild-type and TREM2-deficient mice and analyzing their responses to anti-PD-1 therapy under co-culture and isolated conditions. Through oral administration experiments and the use of different antibiotics, they determined the role of the intestinal microbiota in the response to anti-PD-1 therapy.

Research Conclusions

TREM2 plays a crucial role in regulating the response to anti-PD-1 therapy, and its deficiency can enhance tumor immunotherapy through the amplification of inflammatory intestinal macrophages and specific microbiota. Future research may focus on gaining a deeper understanding of the interactions between these cells and molecules and how to leverage these findings in clinical settings to improve therapeutic outcomes.