肿瘤内多食鞘氨醇杆菌通过抑制肿瘤免疫监视促进三阴性乳腺癌进展。
Intra-tumoral sphingobacterium multivorum promotes triple-negative breast cancer progression by suppressing tumor immunosurveillance.
作者信息
Mai Zhikai, Fu Liwu, Su Jiyan, To Kenneth K W, Yang Chuansheng, Xia Chenglai
机构信息
Foshan Maternity and Child Healthcare Hospital; School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 515150, China.
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Esophageal Cancer Institute, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.
出版信息
Mol Cancer. 2025 Jan 8;24(1):6. doi: 10.1186/s12943-024-02202-9.
BACKGROUND
Intratumor-resident bacteria represent an integral component of the tumor microenvironment (TME). Microbial dysbiosis, which refers to an imbalance in the bacterial composition and bacterial metabolic activities, plays an important role in regulating breast cancer development and progression. However, the impact of specific intratumor-resident bacteria on tumor progression and their underlying mechanisms remain elusive.
METHODS
16S rDNA gene sequencing was used to analyze the cancerous and paracancerous tissues from breast cancer patients. The mouse models of bearing 4T1 cell tumors were employed to assess the influence of bacterial colonization on tumor growth. Tissue infiltration of regulatory T (Treg) cells and CD8 T cells was evaluated through immunohistochemistry and flow cytometric analysis. Comparative metabolite profiling in mice tumors was conducted using targeted metabolomics. Differential genes of tumor cells stimulated by bacteria were analyzed by transcriptomics and validated by qPCR assay.
RESULTS
We found that Sphingobacterium displayed high abundance in cancerous tissues. Intra-tumoral colonization of Sphingobacterium multivorum (S. multivorum) promoted tumor progression in 4T1 tumor-bearing mice. Moreover, S. multivorum diminished the therapeutic efficacy of αPD-1 mAb, which was associated with the increase of regulatory T cell (Treg) infiltration, and decrese of the CD8 T cell infiltration. Targeted metabolomics revealed a conspicuous reduction of propionylcarnitine in tumors colonized by S. multivorum Furthermore, the combination of metabolite propionylcarnitine and S. multivorum shown to suppress tumor growth compared that in S. multivorum alone in vivo. Mechanistically, S. multivorum promoted the secretion of chemokines CCL20 and CXCL8 from tumor cells. CCL20 secreted into the TME facilitated the recruitment of Treg cells and reduced CD8 T cell infiltration, thus promoting tumor immune escape.
CONCLUSIONS
This study reveals S. multivorum suppresses immune surveillance within the TME, thereby promoting breast cancer progression.
背景
肿瘤内驻留细菌是肿瘤微环境（TME）的一个重要组成部分。微生物群落失调是指细菌组成和细菌代谢活动的失衡，在调节乳腺癌的发生和发展中起重要作用。然而，特定肿瘤内驻留细菌对肿瘤进展的影响及其潜在机制仍不清楚。
方法
采用16S rDNA基因测序分析乳腺癌患者的癌组织和癌旁组织。利用携带4T1细胞肿瘤的小鼠模型评估细菌定植对肿瘤生长的影响。通过免疫组织化学和流式细胞术分析评估调节性T（Treg）细胞和CD8 T细胞的组织浸润情况。使用靶向代谢组学对小鼠肿瘤进行比较代谢物谱分析。通过转录组学分析细菌刺激的肿瘤细胞的差异基因，并通过qPCR测定进行验证。
结果
我们发现鞘氨醇杆菌在癌组织中丰度较高。多食鞘氨醇杆菌（S. multivorum）在肿瘤内定植促进了4T1荷瘤小鼠的肿瘤进展。此外，多食鞘氨醇杆菌降低了αPD-1单克隆抗体的治疗效果，这与调节性T细胞（Treg）浸润增加和CD8 T细胞浸润减少有关。靶向代谢组学显示，多食鞘氨醇杆菌定植的肿瘤中丙酰肉碱显著减少。此外，体内实验表明，丙酰肉碱和多食鞘氨醇杆菌联合使用比单独使用多食鞘氨醇杆菌更能抑制肿瘤生长。机制上，多食鞘氨醇杆菌促进肿瘤细胞分泌趋化因子CCL20和CXCL8。分泌到TME中的CCL20促进了Treg细胞的募集并减少了CD8 T细胞的浸润，从而促进了肿瘤免疫逃逸。
结论
本研究揭示多食鞘氨醇杆菌抑制TME内的免疫监视，从而促进乳腺癌进展。
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