Hao Wu: 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. Electronic address: 3345@hrbmu.edu.cn.
Jiena Liu: 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. Electronic address: liujienana@163.com.
Xing-Hua Zhang: Genomics Research Center, State Key Laboratory of Biomedicine-Pharmaceutics of China, College of Pharmacy, Harbin Medical University, Harbin, China; Key Laboratory of Gut Microbiota and Pharmacogenomics of Heilongjiang Province, Harbin Medical University, Harbin, China; HMU-UCCSM Centre for Infection and Genomics, Harbin Medical University, Harbin, China; National Key Laboratory of Frigid Zone Cardiovascular Diseases, Harbin 150081, China.
Shengye Jin: 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.
Ping Li: The Third Affiliated Hospital of Beijing University of Chinese Medicine, Beijing, China.
Huidi Liu: Genomics Research Center, State Key Laboratory of Biomedicine-Pharmaceutics of China, College of Pharmacy, Harbin Medical University, Harbin, China; Key Laboratory of Gut Microbiota and Pharmacogenomics of Heilongjiang Province, Harbin Medical University, Harbin, China; HMU-UCCSM Centre for Infection and Genomics, Harbin Medical University, Harbin, China; National Key Laboratory of Frigid Zone Cardiovascular Diseases, Harbin 150081, China; Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, AB, Canada.
Liuying Zhao: 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.
Jianyu Wang: 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.
Shilu Zhao: 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.
Hong-Da Tian: Genomics Research Center, State Key Laboratory of Biomedicine-Pharmaceutics of China, College of Pharmacy, Harbin Medical University, Harbin, China; Key Laboratory of Gut Microbiota and Pharmacogenomics of Heilongjiang Province, Harbin Medical University, Harbin, China; HMU-UCCSM Centre for Infection and Genomics, Harbin Medical University, Harbin, China; National Key Laboratory of Frigid Zone Cardiovascular Diseases, Harbin 150081, China.
Jin-Ru Lai: Genomics Research Center, State Key Laboratory of Biomedicine-Pharmaceutics of China, College of Pharmacy, Harbin Medical University, Harbin, China; Key Laboratory of Gut Microbiota and Pharmacogenomics of Heilongjiang Province, Harbin Medical University, Harbin, China; HMU-UCCSM Centre for Infection and Genomics, Harbin Medical University, Harbin, China; National Key Laboratory of Frigid Zone Cardiovascular Diseases, Harbin 150081, China.
Yi Hao: Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, China.
Gui-Rong Liu: Genomics Research Center, State Key Laboratory of Biomedicine-Pharmaceutics of China, College of Pharmacy, Harbin Medical University, Harbin, China; Key Laboratory of Gut Microbiota and Pharmacogenomics of Heilongjiang Province, Harbin Medical University, Harbin, China; HMU-UCCSM Centre for Infection and Genomics, Harbin Medical University, Harbin, China; National Key Laboratory of Frigid Zone Cardiovascular Diseases, Harbin 150081, China.
Kaijian Hou: School of Public Health, Shantou University, Shantou, China; Longhu People's Hospital, Shantou, China. Electronic address: kaijianhou@126.com.
Meisi Yan: Department of Pathology, Harbin Medical University, Harbin, China. Electronic address: msyan@hrbmu.edu.cn.
Shu-Lin Liu: Genomics Research Center, State Key Laboratory of Biomedicine-Pharmaceutics of China, College of Pharmacy, Harbin Medical University, Harbin, China; Key Laboratory of Gut Microbiota and Pharmacogenomics of Heilongjiang Province, Harbin Medical University, Harbin, China; HMU-UCCSM Centre for Infection and Genomics, Harbin Medical University, Harbin, China; National Key Laboratory of Frigid Zone Cardiovascular Diseases, Harbin 150081, China; Department of Microbiology, Immunology and Infectious Diseases, University of Calgary, Calgary, AB, Canada. Electronic address: slliu@hrbmu.edu.cn.
Da Pang: 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. Electronic address: pangda@ems.hrbmu.edu.cn.
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.
