Single-cell transcriptomic analysis reveals gut microbiota-immunotherapy synergy through modulating tumor...

Area of Science:

• Immunology
• Microbiology
• Cancer Research

Background:

• Immune checkpoint inhibitors (ICIs) are vital cancer therapies, but their efficacy is influenced by the gut microbiota.
• The precise single-cell mechanisms underlying gut microbiota-ICI synergy remain largely unknown.
• Understanding these mechanisms is crucial for optimizing immunotherapy outcomes.

Purpose of the Study:

• To investigate the synergistic effects of gut microbiota and ICIs on the tumor microenvironment (TME) at a single-cell level.
• To elucidate the cellular interactions and molecular pathways involved in this synergy.
• To identify potential therapeutic targets for enhancing immunotherapy.

Main Methods:

• Single-cell RNA sequencing (scRNA-seq) of the TME in mouse models.
• Validation studies including fecal microbiota transplantation and genetic depletion of specific cell populations (Spp1+ TAMs).
• Analysis of cellular interactions, metabolic pathways, and signaling cascades (e.g., NF-κB).

Main Results:

• Combined gut microbiota and ICIs increased CD8+, CD4+, and γδ T cells, reduced glycolysis, and reversed CD8+ T cell exhaustion.
• Macrophage reprogramming occurred from M2 Spp1+ TAMs to Cd74+ APCs, with a negative correlation between these subtypes.
• Depletion of Spp1+ TAMs enhanced ICI efficacy and T cell infiltration, irrespective of microbiota status.
• A proposed γδ T cell-APC-CD8+ T cell axis mediated synergy via CD40-CD40L and CD86-CD28 interactions.

Conclusions:

• Gut microbiota and ICIs synergistically enhance antitumor responses by modulating TME cellular composition and function.
• Spp1+ TAMs negatively impact immunotherapy, while Cd74+ TAMs may act as beneficial APCs.
• Targeting the γδ T cell-APC-CD8+ T cell axis and macrophage reprogramming presents a promising strategy for improving ICI therapy.