Fusobacterium nucleatum facilitates anti-PD-1 therapy in microsatellite stable colorectal cancer.
Cancer Cell
; 42(10): 1729-1746.e8, 2024 Oct 14.
Article
em En
| MEDLINE
| ID: mdl-39303724
ABSTRACT
Microsatellite stable (MSS) colorectal cancers (CRCs) are often resistant to anti-programmed death-1 (PD-1) therapy. Here, we show that a CRC pathogen, Fusobacterium nucleatum (Fn), paradoxically sensitizes MSS CRC to anti-PD-1. Fecal microbiota transplantation (FMT) from patients with Fn-high MSS CRC to germ-free mice bearing MSS CRC confers sensitivity to anti-PD-1 compared to FMT from Fn-low counterparts. Single Fn administration also potentiates anti-PD-1 efficacy in murine allografts and CD34+-humanized mice bearing MSS CRC. Mechanistically, we demonstrate that intratumoral Fn generates abundant butyric acid, which inhibits histone deacetylase (HDAC) 3/8 in CD8+ T cells, inducing Tbx21 promoter H3K27 acetylation and expression. TBX21 transcriptionally represses PD-1, alleviating CD8+ T cell exhaustion and promoting effector function. Supporting this notion, knockout of a butyric acid-producing gene in Fn abolishes its anti-PD-1 boosting effect. In patients with MSS CRC, high intratumoral Fn predicts favorable response to anti-PD-1 therapy, indicating Fn as a potential biomarker of immunotherapy response in MSS CRC.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Neoplasias Colorretais
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Fusobacterium nucleatum
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Linfócitos T CD8-Positivos
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Receptor de Morte Celular Programada 1
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Transplante de Microbiota Fecal
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Inibidores de Checkpoint Imunológico
Limite:
Animals
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Female
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Humans
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Male
Idioma:
En
Revista:
Cancer Cell
Assunto da revista:
NEOPLASIAS
Ano de publicação:
2024
Tipo de documento:
Article
País de publicação:
Estados Unidos