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Chang Wei Qing Decoction enhances the anti-tumor effect of pd-1 inhibitor therapy by regulating the immune microenvironment and gut microbiota in colorectal cancer

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Chinese Journal of Natural Medicines 2023年第5期21卷 333-345页

作者： WANG Ting WU Linguangjin WANG Shuyun SHI Xiaolan LIU Hui DENG Wanli Department of Oncology Putuo HospitalShanghai University of Traditional Chinese MedicineShanghai 200062China Shanghai University of Traditional Chinese Medicine Shanghai 201203China

The anti-tumor effect of anti-pd-1 antibody has long been shown to be strongly related to the tumor immune microenvironment(TIME).This study aimed to mechanistically assess whether Chang Wei Qing(CWQ)Decoction can enhance the anti-tumor effect of pd-1 inhibitor therapy.pd-1 inhibitor therapy showed the significant anti-tumor effect in patients with mismatch repairdeficient/microsatellite instability-high(dMMR/MSI-H)colorectal cancer(CRC),rather than those with mismatch repairproficient/microsatellite stable(pMMR/MSS)CRC.Hence,immunofluorescence double-label staining was utilized to explore the difference in the TIME between dMMR/MSI-H and pMMR/MSS CRC patients.Flow cytometry was used to analyze T-lymphocytes in tumors from mice.Western blot was used to measure the expression of pd-L1 protein in mouse tumors.The intestinal mucosal barrier of mice was evaluated by hematoxylin-eosin staining and immunohistochemistry.16S rRNA-gene sequencing was used to examine the structure of the gut microbiota in mice.Subsequently,Spearman’s correlation analysis was used to analyze the relationship between the gut microbiota and tumor-infiltrating T-lymphocytes.The results showed that dMMR/MSI-H CRC patients had more CD8+T cells and higher expression of pd-1 and pd-L1 proteins.In vivo,CWQ enhanced the anti-tumor effect of anti-pd-1 antibody and increased the infiltration of CD8+and pd-1+CD8+T cells in tumors.Additionally,the combination of CWQ with anti-pd-1 antibody resulted in lower inflammation in the intestinal mucosa than that induced by anti-pd-1 antibody alone.CWQ and anti-pd-1 antibody co-treatment upregulated pd-L1 protein and reduced the abundance of Bacteroides in the gut microbiota but increased the abundance of Akkermansia,Firmicutes,and Actinobacteria.Additionally,the proportion of infiltrated CD8+pd-1+,CD8+,and CD3+T cells were found to be positively correlated with the abundance of Akkermansia.Accordingly,CWQ may modulate the TIME by modifying the gut microbiota and consequently enhance the anti-tumor effect of pd-

关键词： Tumor immune microenvironment pd-1 inhibitor therapy Gut microbiota CD8+T cells Chang Wei Qing

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