Fusobacterium nucleatum facilitates anti-PD-1 therapy in microsatellite stable colorectal cancer
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<sup>+</sup>-humanized mice bearing MSS CRC. Mechanistically, we demonstrate that intratumoral Fn generates abundant butyric acid, which inhibits histone deacetylase (HDAC) 3/8 in CD8<sup>+</sup> T cells, inducing Tbx21 promoter H3K27 acetylation and expression. TBX21 transcriptionally represses PD-1, alleviating CD8<sup>+</sup> 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.
Authors
- Huanlong Qin (ORCID: https://orcid.org/0000-0002-3956-7595)
- Meinong Liang
- Chuanfa Liu (ORCID: https://orcid.org/0000-0001-5140-6041)
- Joseph J.�Y. Sung (ORCID: https://orcid.org/0000-0003-3125-5199)
- Xiaoxing Li (ORCID: https://orcid.org/0000-0001-8791-7505)
- Harry Cheuk-Hay Lau (ORCID: https://orcid.org/0000-0003-3581-2909)
- Lixia Xu (ORCID: https://orcid.org/0000-0002-1818-6267)
- Bing Liao (ORCID: https://orcid.org/0000-0001-8998-4146)
- Song Wu (ORCID: https://orcid.org/0000-0002-1314-8018)
- Xiang Zhang (ORCID: https://orcid.org/0000-0001-6047-0934)
- Na Wang (ORCID: https://orcid.org/0009-0004-8231-2071)
- Jun Qing Yu (ORCID: https://orcid.org/0000-0001-5008-2153)
- Xueliang Wang (ORCID: https://orcid.org/0000-0003-2834-9370)
- Yongxin Zhang (ORCID: https://orcid.org/0000-0003-3173-4560)
- Yaohui Gao
- Y. Q. Fang (ORCID: https://orcid.org/0000-0003-4917-4311)
- Junlin Wang (ORCID: https://orcid.org/0000-0003-1824-6159)
- Wei Liang (ORCID: https://orcid.org/0000-0001-5195-5761)
- Chi Chun Wong (ORCID: https://orcid.org/0000-0003-4520-2688)
- Fang Jingyuan
- Miao Fan
- Lei Song
- Mengmiao Mo
- Tao Yang (ORCID: https://orcid.org/0000-0002-7795-6081)
Institutions
- Tongji University (CN)
- Sun Yat-sen University (CN)
- Chinese University of Hong Kong (HK)
- Shanghai Jiao Tong University (CN)
- Renji Hospital (CN)
- Chinese University of Hong Kong, Shenzhen (CN)
- The First Affiliated Hospital, Sun Yat-sen University (CN)
- Shanghai Tenth People's Hospital (CN)
- State Key Laboratory of Oncogene and Related Genes (CN)
Publication Details
- Journal
- Cancer Cell
- Published
- 2024-09-19
- DOI
- https://doi.org/10.1016/j.ccell.2024.08.019
- Citations
- 160
- Primary Topic
- Cancer Immunotherapy and Biomarkers
- Type
- article
- Field-Weighted Citation Impact
- 45.21
Funders
- National Key Research and Development Program of China Stem Cell and Translational Research