Tong-Xie-Yao-Fang promotes dendritic cells maturation and retards tumor growth in colorectal cancer mice with chronic restraint stress

Depression is one of the important risk factors that accelerate the progression of colorectal cancer (CRC). Tong-Xie-Yao-Fang (TXYF) is a widely used classical formula for treating psychiatric-related intestinal diseases in traditional Chinese medicine, that is composed of four different herbs: Atractylodes macrocephala Koidz. (Baizhu), Paeonia lactiflora Pall. (Baishaoyao), Citrus reticulata Blanco (Chenpi), Saposhnikovia divaricata (Turcz.) Schischk (Fangfeng). TXYF has over a hundred years of history and can significantly improve depression and reduce intestinal symptoms. However, the intervention effect and mechanism of TXYF on colorectal cancer accompanied by psychological stress are not still clear.This study investigated the therapeutic effect of TXYF on CRC mice with chronic restraint stress (CRS) and to explore its mechanism.We constructed a mouse model of chronic stress by CRS and subcutaneous injection of CT26-Luc cells, and administered TXYF by gavage. We measured the body weight, tumor size, and tumor weight of each group of mice. The tumor growth was monitored dynamically of by vivo bioluminescence analysis. The depressive state of each group of mice were evaluated by tail suspension test, forced swimming test, and hormone level changes. We used flow cytometry to detect the ratio of CD4+ T cells, CD8+ T cells, Th1 cells, Th2 cells, and dendritic cells (DCs) phenotype (MHC II, CD80, and CD86) and chemotaxis ability (CXCR4 and CCR7) of in peripheral blood and tumor tissue. the levels of IL-12, IL-18, Th1 cytokines, and Th2 cytokines in the serum of each group of mice were determined by ELISA.TXYF can improve the body weight of CRC mice with CRS, inhibit tumor volume and weight, alleviate depressive state, upregulate 5-HT levels, and inhibit HPA axis hormone secretion. The results of flow cytometry showed that TXYF can promote the maturation of DCs phenotype and function, enhance antigen presentation ability, increase the ratio of CD4+ T cells and CD4+/CD8+ T cells, and shift Th1/Th2 balance towards Th1 cells, thus increasing serum levels of IFN-γ, IL-18, IL-2, and IL-12, while decreasing serum levels of IL-4 and IL-10, and effectively triggering T cell-mediated immune response.This study shows that TXYF inhibits the growth of tumors in CRC mice with CRS by stimulating immune response. The mechanism may be inhibiting the HPA axis and promoting DCs maturation, thus activating T cells and enhancing anti-tumor immune response, ultimately preventing the progression of CRC.