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

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. Overall design: RNA-seq profiling of YB328, P. vulgatus-treated and untreated BMDCs.