Fusobacterium nucleatum facilitates anti-PD-1 therapy in microsatellite stable colorectal cancer

  • Cancer Cell. 2024 Oct 14;42(10):1729-1746.e8. doi: 10.1016/j.ccell.2024.08.019.
Xueliang Wang  1 ,  Yi Fang  2 ,  Wei Liang  2 ,  Chi Chun Wong  3 ,  Huanlong Qin  4 ,  Yaohui Gao  5 ,  Meinong Liang  2 ,  Lei Song  2 ,  Yongxin Zhang  2 ,  Miao Fan  2 ,  Chuanfa Liu  3 ,  Harry Cheuk-Hay Lau  3 ,  Lixia Xu  6 ,  Xiaoxing Li  2 ,  Wu Song  7 ,  Junlin Wang  2 ,  Na Wang  2 ,  Tao Yang  2 ,  Mengmiao Mo  2 ,  Xiang Zhang  3 ,  Jingyuan Fang  8 ,  Bing Liao  9 ,  Joseph J Y Sung  10 ,  Jun Yu  11
Affiliations
  • 1. Department of Oncology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Institute of Digestive Disease and The Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China; Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
  • 2. Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
  • 3. Institute of Digestive Disease and The Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China.
  • 4. Department of Gastrointestinal Surgery, Shanghai Tenth People's Hospital, Tongji University, Shanghai, China.
  • 5. Department of Pathology, Shanghai Tenth People's Hospital, Tongji University, Shanghai, China.
  • 6. Department of Oncology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
  • 7. Department of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
  • 8. Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
  • 9. Department of Pathology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
  • 10. Institute of Digestive Disease and The Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China; Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore.
  • 11. Department of Oncology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Institute of Digestive Disease and The Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China; Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. Electronic address: [email protected].
PMID: 39303724 DOI: 10.1016/j.ccell.2024.08.019
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.

Keywords
Fusobacterium nucleatum; PD-1; anti-PD-1 immunotherapy; autologous T cell and organoid co-culture system; butyric acid; butyric acid-HDAC3/8-H3K27ac-TBX21-PD-1 signaling pathway; germ-free immunohumanized mice; specific pathogen-free immunohumanized mice.
Products
Inhibitors & Agonists
Other Products