Williams Cancer Institute

The Role of Gut Microbiota and Tumor-Associated Macrophages in Enhancing Anti–PD-1 Immunotherapy

In recent years, the interplay between the gut microbiota and immune responses has gained significant attention in cancer research. One of the key areas of focus has been how these interactions influence the effectiveness of anti–programmed cell death protein 1 (PD-1) immune checkpoint blockade, a type of immunotherapy used to treat various cancers. A recent study has shed light on how tumor-associated macrophages (TAMs) and the gut microbiota can be manipulated to improve tumor responses to anti–PD-1 therapy.

Reprogramming TAMs to Enhance Tumor Response

TAMs play a crucial role in the tumor microenvironment, often promoting tumor growth and suppressing immune responses. The study highlights that reprogramming TAMs by blocking or deleting the macrophage receptor triggering receptor on myeloid cells 2 (TREM2) can significantly attenuate tumor growth. This reprogramming enhances the tumor elimination capabilities of anti–PD-1 therapy. In essence, the absence of functional TREM2 in mice boosts the effectiveness of anti–PD-1 treatment, leading to better tumor control.

The Gut Microbiota Connection

One of the most intriguing findings of the study is the connection between TREM2 deficiency and changes in the gut microbiota. When TREM2-deficient mice were treated with anti–PD-1 therapy, there was a notable induction of proinflammatory programs in intestinal macrophages, along with a significant expansion of the gut bacterium Ruminococcus gnavus. This expansion appears to play a pivotal role in enhancing the immune response against tumors.

To further explore this connection, the researchers conducted experiments where they gavaged wild-type mice with R. gnavus. Remarkably, this treatment alone enhanced the tumor elimination effects of anti–PD-1 therapy, mimicking the results observed in TREM2-deficient mice. This suggests that R. gnavus could be a key player in modulating the intestinal immune environment to favor an enhanced anti-tumor response.

The Proinflammatory Intestinal Environment

The presence of a proinflammatory intestinal environment was linked with several beneficial changes in the immune system. Specifically, there was an increase in the expansion, circulation, and migration of tumor necrosis factor (TNF)-producing CD4+ T cells to the tumor bed. These immune cells are critical for mounting an effective anti-tumor response, indicating that modulating the gut microbiota can have systemic effects that improve the efficacy of immunotherapy.

TREM2 as a Remote Controller
The study underscores the role of TREM2 in remotely controlling the effectiveness of anti–PD-1 immune checkpoint blockade. By modulating the intestinal immune environment and gut microbiota, TREM2 can influence the overall immune response to tumors. This highlights a novel mechanism through which the gut microbiota and immune system interact to affect cancer therapy outcomes.

Ruminococcus gnavus as a Potential Probiotic Agent

The findings of this study point to Ruminococcus gnavus as a promising probiotic agent that could be used to enhance the responsiveness to anti–PD-1 therapy. By promoting a proinflammatory intestinal environment and boosting the migration of TNF-producing CD4+ T cells to the tumor site, R. gnavus could play a critical role in improving cancer treatment outcomes.

Reference: Blanda Di Luccia, Martina Molgora, Darya Khantakova, Natalia Jaeger, Hao-Wei Chang, Rafael S. Czepielewski, Beth A. Helmink, Emily J. Onufer, José L. Fachi, Bishan Bhattarai, Tihana Trsan, Patrick F. Rodrigues, JinChao Hou, Jennifer K. Bando, Cristiane Sécca da Silva, Marina Cella, Susan Gilfillan, Robert D. Schreiber, Jeffrey I. Gordon, Marco Colonna. 17 May 2024. TREM2 deficiency reprograms intestinal macrophages and microbiota to enhance anti–PD-1 tumor immunotherapy. https://www.science.org/doi/10.1126/sciimmunol.adi5374

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