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

Background

Immune checkpoint inhibitors (CPIs), such as drugs that block programmed cell death protein-1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated protein-4 (CTLA-4), have been successfully used to activate anti-tumor T cell responses to treat various types of cancer. However, despite many patients showing durable responses to CPIs, a significant number of patients remain unresponsive or experience relapses, prompting scientists to explore complementary therapeutic avenues to improve the efficacy of CPIs. Tumor-associated macrophages (TAMs) support the survival, proliferation, and angiogenesis of tumor cells and suppress immune responses, thereby undermining the efficacy of CPIs. Blocking or deleting the macrophage receptor triggering receptor expressed on myeloid cells-2 (TREM2), which is extensively expressed on TAMs, can reduce the immunosuppressive functions of TAMs and enhance the anti-tumor T cell response induced by anti-PD-1 therapy.

Another strategy to enhance CPI therapy effectiveness is by targeting the gut microbiota. Studies have shown that the composition of the gut microbiota is closely related to the efficacy of CPIs in clinical models and cancer patients. Fecal microbiota transplantation (FMT) or oral administration of specific bacteria can increase the sensitivity of mouse models to CPIs. Human studies have found an association between the gut microbiota and the efficacy of CPIs, and recent evidence suggests a causal relationship. Given this, the study in this paper attempts to explore how TREM2 deficiency affects the gut microbiota and its impact on the efficacy of anti-PD-1 therapy, providing new perspectives for future cancer immunotherapy.

Paper Overview

This paper was co-authored by Blanda Di Luccia, Martina Molgora, Darya Khantakova, and others. The study was conducted through collaborations between Washington University School of Medicine, Stanford University, University of Texas MD Anderson Cancer Center, and other institutions. The paper was published in Science Immunology on May 17, 2024.

Research Process

In this study, scientists used 8-week-old TREM2+/+ and TREM2−/− mice for experiments. These mice were either cohoused or separated and were inoculated with subcutaneous tumor cells. The experimental design included the following steps:

Step 1: Cohousing and Separate Housing

Researchers cohoused TREM2+/+ and TREM2−/− mice from birth and separated them after tumor cell inoculation. In one group, these mice remained cohoused (coh), while in another group, these mice were separated (sep) after tumor injection.

Step 2: Anti-PD-1 Therapy

After tumor cell inoculation, the mice were further divided into groups receiving or not receiving anti-PD-1 therapy. The tumor growth in different groups of mice was recorded, showing that TREM2-deficient mice exhibited enhanced tumor response under anti-PD-1 therapy.

Step 3: Impact of Gut Microbiota

To determine whether the gut microbiota plays a key role in the enhanced efficacy of anti-PD-1 therapy in TREM2-deficient mice, researchers used multiple strategies to alter the gut microbiota of mice. For example, they treated mice with antibiotics and conducted microbiota transfer experiments, observing that changes in the gut microbiota under the background of anti-PD-1 therapy and TREM2 deficiency significantly affected tumor control.

Step 4: Study of Cellular and Molecular Mechanisms

Researchers used single-cell RNA sequencing (scRNA-seq) to analyze macrophages obtained from the gut and immune cells isolated from tumors, finding that TREM2 deficiency led to gut macrophages exhibiting a pro-inflammatory phenotype and observed the accumulation of tumor necrosis factor (TNF)-producing CD4+ T cells.

Research Results

Main Results:

1. TREM2 Deficiency Enhances the Efficacy of Anti-PD-1 Therapy: In TREM2−/− mice, anti-PD-1 therapy significantly inhibited tumor growth, far outperforming TREM2+/+ mice.

2. Changes in Gut Microbiota Composition: Anti-PD-1 therapy induced specific changes in the gut microbiota in TREM2−/− mice, particularly the expansion of Ruminococcus gnavus. The study also found that transplanting R. gnavus into wild-type mice could reproduce the anti-tumor effects observed in TREM2-deficient mice.

3. Reprogramming of Gut Macrophages: TREM2 deficiency led to the reprogramming of gut macrophages towards a pro-inflammatory phenotype, promoting the migration of TNF-producing CD4+ T cells to the tumor site.

4. Changes in Systemic Immune Response: TREM2−/− mice exhibited a more inflamed gut environment, which contributed to the enhanced efficacy of anti-PD-1 therapy.

Research Conclusions

The combined action of anti-PD-1 therapy and TREM2 deficiency led to significant changes in the gut microbiota and gut immune environment. These changes included the expansion of specific bacterial populations (such as R. gnavus) and their beneficial effects on the tumor immune environment. The results suggest that targeting the gut microbiota or specific immune pathways could further improve the response of cancer patients to immune checkpoint inhibitors.

Research Highlights

1. Novelty of the Study: For the first time, the interaction between TREM2 and the gut microbiota and their impact on the efficacy of anti-PD-1 therapy has been revealed.

2. Practical Application Value: Provides a theoretical basis for developing new strategies to enhance the efficacy of immune checkpoint inhibitors, especially through the regulation of the gut microbiota.

3. Methodological Innovation: Utilizes single-cell RNA sequencing to reveal the specific mechanisms of TREM2 deficiency in the gut immune environment and verifies the function of specific bacterial populations through microbiota transplantation.

Significance and Value of the Paper

This study not only provides new ideas for cancer immunotherapy but also emphasizes the important role of the gut microbiota in immune regulation. In the future, optimizing the gut microbiota or combining TREM2 inhibitors may further improve the efficacy of anti-PD-1 therapy, bringing new hope for cancer treatment. Moreover, this study provides a solid foundation for exploring more treatment strategies related to the gut microbiota.