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Identifying mechanisms for augmenting antitumour efficacy of PD-1 blockade therapy by gut microbiota

ABSTRACT: The gut microbiota is related to the antitumour efficacy of immune checkpoint blockade, but the mechanism(s) of action have not been fully elucidated. Here, we show that a novel Ruminococcaceae strain (designated YB328) isolated from the faeces of patients who responded to programmed cell death 1 (PD-1) blockade primes/activates tumour-specific CD8+ T cells through stimulation/maturation of CD103+CD11b- conventional dendritic cells (cDCs) which migrate from the gut to the tumour microenvironment (TME). YB328 administration improved the antitumour efficacy of PD-1 blockade even when it was added to faecal transplantation from non-responder patients in animal models. YB328 promoted the IRF8-driven differentiation of CD103+CD11b- cDCs expressing multiple Toll-like receptors, which received additional stimulation/maturation signals from other bacteria, and the accumulation of these DCs in tumour lesions. These CD103+CD11b- cDCs prolonged engagement with cognate antigen-specific CD8+ T cells, which induced the activation of CD8+ T cells specific for diverse tumour antigens and fostered PD-1 expression through NFATc1 nuclear translocation, thereby leading to an increase in PD-1+CD8+ T cells harbouring a broader T-cell receptor repertoire in the TME. We propose that the gut microbiota augments antitumour immunity by accelerating the differentiation/maturation and migration of DCs to increase CD8+ T cells responding to diverse tumour antigens.

ORGANISM(S): Mus musculus

PROVIDER: GSE285376 | GEO | 2025/05/06

REPOSITORIES: GEO

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