The Gut Microbiome Drives Endogenous T Cell Activation Following CAR-T Cell Therapy

Area of Science:

• Immunology
• Microbiology
• Oncology

Background:

• Chimeric antigen receptor (CAR)-T cell therapy shows promise for hematological cancers but faces challenges with inconsistent outcomes and incomplete tumor eradication.
• The gut microbiome's influence on CAR-T cell therapy effectiveness is recognized, yet the precise mechanisms remain unclear.

Purpose of the Study:

• To elucidate the role of gut microbiota in modulating CAR-T cell therapy efficacy.
• To identify specific gut bacteria that enhance CAR-T cell antitumor activity.

Main Methods:

• Establishment of a syngeneic CD19+ murine lymphoma model for evaluating CAR-T therapy with endogenous immune cells and gut microbiota.
• Single-cell transcriptomic analysis to assess T cell activation and 16S RNA sequencing to profile gut microbiota composition.
• In vivo supplementation of identified bacterial strains to evaluate their impact on CAR-T therapy outcomes.

Main Results:

• CAR-T cell infusion activated peripheral and gut-infiltrating endogenous CD8+ T cells.
• Significant alterations in gut microbiota composition were observed post-infusion, correlating with CD8+ T cell activation and therapy response.
• The gut bacteria Turicibacter and Parvibactor were identified as critical for effective CAR-T treatment, enhancing CD8+ T cell activation and tumor lysis.

Conclusions:

• Gut microbiome composition is a key determinant of CAR-T cell therapy effectiveness.
• Supplementation with Turicibacter and Parvibactor can improve CAR-T cell therapy outcomes by boosting endogenous immune responses.
• These findings highlight specific gut bacteria as potential targets for enhancing CAR-T cell immunotherapy.