Mechanism of Qizhen decoction-mediated maturation of DC cells to activate the IL-12/JAK2/STAT4 pathway to sensitise PD-1 inhibitors in the treatment of colorectal cancer

Abstract

Ethnopharmacological relevanceTraditional Chinese medicine has been utilized to treat colorectal cancer (CRC). Qizhen decoction (QZD), a potential compound prescription of traditional Chinese medicine, possesses multiple biological activities. It has been used to treat CRC in clinical practice and has been proven to be effective. Aim of the studyTo investigate the impact of QZD supported by intestinal flora in combination with PD-1 inhibitor on colorectal cancer, and to elucidate the mechanism by which QZD enhances the sensitivity of PD-1 inhibitor against colorectal cancer. Materials and methodsObservation of Intestinal Flora Mediating the Effect of QZD Combined with PD-1 Inhibitor in the Treatment of Colorectal Cancer. We used Flow cytometry and qPCR to detect the effect of QZD combined with PD-1 inhibitor on the activation of effector T cells in a wild mouse model of colorectal cancer. In wild and germ-free mouse models, the differences in inflammatory factors, pathological change, body mass, colorectal length, and tumour load were observed. In the study of the mechanism of QZD combined with PD-1 inhibitor in the treatment of colorectal cancer, the study evaluated the abundance of Akkermansia, the phenotypes of effector T cells and DC cells, as well as inflammatory factors in each group of mice to determine whether Akkermansia played a role in activating DC cells. Based on the JAK2/TYK2/STAT4 pathway, the mechanism of PD-1 inhibitor sensitisation by QZD in colorectal cancer was further investigated. ResultsWe found that QZD combined with PD-1 inhibitor could improve the therapeutic effect on colorectal cancer by inducing more critical immune functions. QZD promotes increased Akkermansia abundance in the gut. Akkermansia promotes maturation of DC cells, and mature DC cells activate the IL-12/JAK2/STAT4 pathway, which significantly activates effector T cells. Akkermansia is key to QZD combined with PD-1 inhibitor-mediated immunity exerting a therapeutic effect on colorectal cancer. ConclusionThe mechanism of action of the QZD sensitizing PD-1 inhibitor is to promote the maturation of DC cells to release IL-12 and activate the JAK2/STAT4 pathway to induce effector T cell activation by increasing the abundance of Akkermansia.