Williams Cancer Institute

The Gut Microbiota and Its Influence on Tumor Response to Anti-PD-1 Immunotherapy

The relationship between the gut microbiota and tumor-associated macrophages (TAMs) plays a crucial role in how tumors respond to anti–programmed cell death protein 1 (PD-1) immune checkpoint blockade. Reprogramming TAMs, either by blocking or deleting the macrophage receptor known as TREM2, can reduce tumor growth. Additionally, the absence of functional TREM2 enhances tumor elimination by anti-PD-1 therapy.

Recent studies in mice have discovered that the combination of anti-PD-1 treatment with TREM2 deficiency triggers pro-inflammatory programs in intestinal macrophages. This also leads to a simultaneous expansion of a specific bacterium in the gut microbiota, Ruminococcus gnavus. Administering this bacterium to wild-type mice showed an improvement in anti-PD-1 mediated tumor elimination, replicating the effects observed in the absence of TREM2.

A pro-inflammatory intestinal environment coincided with the expansion, increased circulation, and migration of TNF-producing CD4+ T cells to the tumor bed. Thus, TREM2 remotely controls the effectiveness of anti-PD-1 immune checkpoint blockade through modulation of the intestinal immune environment and microbiota. This discovery suggests that R. gnavus could be a potential probiotic agent for increasing responsiveness to anti-PD-1 therapy.

The role of TREM2 and the gut microbiota, particularly Ruminococcus gnavus, opens new avenues for improving cancer immunotherapy. This approach not only highlights the importance of the interaction between the immune system and the microbiota but also offers a promising strategy to enhance the efficacy of current cancer treatments.

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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