亚麻籽木脂素与PD-1/PD-L1抑制剂联合使用可通过调节肠道微生物群和宿主免疫力来抑制乳腺癌生长。
The combination of flaxseed lignans and PD-1/ PD-L1 inhibitor inhibits breast cancer growth via modulating gut microbiome and host immunity.
作者信息
Wu Hao, Liu Jiena, Zhang Xing-Hua, Jin Shengye, Li Ping, Liu Huidi, Zhao Liuying, Wang Jianyu, Zhao Shilu, Tian Hong-Da, Lai Jin-Ru, Hao Yi, Liu Gui-Rong, Hou Kaijian, Yan Meisi, Liu Shu-Lin, Pang Da
机构信息
Heilongjiang Clinical Research Center for Breast Cancer, Harbin Medical University Cancer Hospital, Harbin, China; Genomics Research Center, State Key Laboratory of Biomedicine-Pharmaceutics of China, College of Pharmacy, Harbin Medical University, Harbin, China.
Heilongjiang Clinical Research Center for Breast Cancer, Harbin Medical University Cancer Hospital, Harbin, China; Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, China.
出版信息
Drug Resist Updat. 2025 May;80:101222. doi: 10.1016/j.drup.2025.101222. Epub 2025 Feb 28.
BACKGROUND
Patients with breast cancer (BC) who benefit from the PD-1/PD-L1 inhibitor (PDi) is limited, necessitating novel strategies to improve immunotherapy efficacy of BC. Here we aimed to investigate the inhibitory effects of flaxseed lignans (FL) on the biological behaviors of BC and evaluate the roles of FL in enhancing the anticancer effects of PDi.
METHODS
HPLC was used to detect the content of enterolactone (ENL), the bacterial transformation product of FL. Transcript sequencing was performed and identified CD38 as a downstream target gene of ENL. CD38-overexpressing cells were constructed and cell proliferation, colony formation, wound healing and transwell assays were used to assess the function of ENL/CD38 axis on BC cells in vitro. Multiplexed immunohistochemistry (mIHC) and CyTOF were used to detect the changes of the tumor immune microenvironment (TIM). 16S rDNA sequencing was used to explore the changes of gut microbiota in mice. A series of in vivo experiments were conducted to investigate the anticancer effects and mechanisms of FL and PDi.
RESULTS
FL was converted to ENL by gut microbiota and FL administration inhibited the progression of BC. ENL inhibited the malignant behaviors of BC by downregulating CD38, a key gene associated with immunosuppression and PD-1/PD-L1 blockade resistance. The mIHC assay revealed that FL administration enhanced CD3, CD4 and CD8 cells and reduced F4/80 cells in TIM. CyTOF confirmed the regulatory effects of FL and FL in combination with PDi (FLcPDi) on TIM. In addition, 16S rDNA analysis demonstrated that FLcPDi treatment significantly elevated the abundance of Akkermansia and, importantly, Akkermansia administration enhanced the response to PDi in mice treated with antibiotics.
CONCLUSIONS
The FL/ENL/CD38 axis inhibited BC progression. FL enhanced the anticancer effects of PDi by modulating gut microbiota and host immunity.
背景
受益于PD-1/PD-L1抑制剂（PDi）的乳腺癌（BC）患者有限，因此需要新的策略来提高BC的免疫治疗效果。在此，我们旨在研究亚麻籽木脂素（FL）对BC生物学行为的抑制作用，并评估FL在增强PDi抗癌作用中的作用。
方法
采用高效液相色谱法检测FL的细菌转化产物肠内酯（ENL）的含量。进行转录组测序并确定CD38为ENL的下游靶基因。构建CD38过表达细胞，并采用细胞增殖、集落形成、伤口愈合和Transwell实验评估ENL/CD38轴对体外BC细胞的功能。采用多重免疫组化（mIHC）和质谱流式细胞术（CyTOF）检测肿瘤免疫微环境（TIM）的变化。采用16S核糖体DNA测序探索小鼠肠道微生物群的变化。进行了一系列体内实验，以研究FL和PDi的抗癌作用及机制。
结果
FL被肠道微生物群转化为ENL，给予FL可抑制BC的进展。ENL通过下调CD38抑制BC的恶性行为，CD38是与免疫抑制和PD-1/PD-L1阻断抗性相关的关键基因。mIHC分析显示，给予FL可增强TIM中的CD3、CD4和CD8细胞，并减少F4/80细胞。CyTOF证实了FL以及FL与PDi联合使用（FLcPDi）对TIM的调节作用。此外，16S rDNA分析表明，FLcPDi治疗显著提高了阿克曼氏菌的丰度，重要的是，给予阿克曼氏菌可增强用抗生素治疗小鼠对PDi的反应。
结论
FL/ENL/CD38轴抑制BC进展。FL通过调节肠道微生物群和宿主免疫增强了PDi的抗癌作用。
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