近日，中山大学于君及其研究组发现，梭杆菌促进微卫星稳定型结直肠癌中抗PD-1疗法的效果。相关论文于2024年9月19日在线发表于国际学术期刊《癌细胞》。

研究人员表示，微卫星稳定型（MSS）结直肠癌（CRC）通常对抗程序性死亡受体-1（PD-1）疗法具有耐药性。

研究人员发现CRC病原体梭杆菌（Fusobacterium nucleatum, Fn）能够逆转这一情况，使MSS CRC对抗PD-1疗法敏感。与来自Fn低表达MSS CRC患者的粪便微生物移植（FMT）相比，来自Fn高表达MSS CRC患者的FMT使携带MSS CRC的无菌小鼠对抗PD-1疗法产生敏感性。单独使用梭杆菌也增强了MSS CRC小鼠异种移植和CD34⁺人源化小鼠中的抗PD-1疗效。

在机制上，研究人员证明梭杆菌在肿瘤内生成大量丁酸，丁酸通过抑制CD8⁺ T细胞中的组蛋白去乙酰化酶（HDAC）3/8，诱导Tbx21启动子H3K27乙酰化和表达。TBX21转录性抑制PD-1，缓解了CD8⁺ T细胞耗竭并促进效应功能。支持这一观点的是，敲除梭杆菌中一个负责产生丁酸的基因后，其增强抗PD-1效果的能力被消除。在MSS CRC患者中，肿瘤内梭杆菌的高表达预示着对抗PD-1疗法的良好反应，提示梭杆菌可能是MSS CRC免疫疗法反应的潜在生物标志物。

附：英文原文

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

Author: Xueliang Wang, Yi Fang, Wei Liang, Chi Chun Wong, Huanlong Qin, Yaohui Gao, Meinong Liang, Lei Song, Yongxin Zhang, Miao Fan, Chuanfa Liu, Harry Cheuk-Hay Lau, Lixia Xu, Xiaoxing Li, Wu Song, Junlin Wang, Na Wang, Tao Yang, Mengmiao Mo, Xiang Zhang, Jingyuan Fang, Bing Liao, Joseph J.Y. Sung, Jun Yu

Issue&Volume: 2024-09-19

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.

DOI: 10.1016/j.ccell.2024.08.019

Source: https://www.cell.com/cancer-cell/abstract/S1535-6108(24)00318-0