The Guiding Effect Of The CCR6-CCL20 Chemokine Axis Is Investigated In Adoptive Immune Cell Therapy Of HCC

Digestive system tumors are a group of solid tumors,including Esophageal squamous cell Hepatocellular carcinoma(HCC),Cholangio carcinoma(CHOL),Pancreatic adenocarcinoma,(PAAD),Esophageal carcinoma,(ESC.A),Gastric carcinoma(GC),Colon adenocarcinoma(COAD),Rectum adenocarcinoma(READ).Digestive tumors are associated with approximately one-third of global cancer morbidity and mortality and represent a serious public health threat.Hepatocellular carcinoma has a primary liver cancer with a high degree of malignancy of digestive system tumors.It is the sixth most prevalent and fourth most lethal malignancy,characterized by a high recurrence rate,a high metastasis rate,and a high degree of malignancy.The adoptive cellular therapy such as Chimeric antigen receptor engineered Tcells(CAR-T)therapy,CAR-modified natural killer(NK)therapy and Chimeric Antigen Receptor Macrophage(CAR-M)therapy.These adoptive cellular therapy have been shown to be effective,which are promising approaches to cure cancer.However,the key problem currently facing the adoptive cellular therapy is the randomized transport of immune cells into the body,which is an important factor limiting the efficacy of adoptive cellular therapy.In previous studies,it was found that when using genetically modified immune cells in the treatment of solid tumors such as digestive tumors,most of the immune cells accumulated in tissues such as liver and lung,but very few or no immune cells were detected on solid tumor tissues.Therefore,finding a solution to solve the problem of randomized transport direction of immune cells after being injected into the human body is the key to enhancing the clinical efficacy of adoptive cellular therapy.Fortunately,there are many chemokines and chemokine receptors in the human body,and their main function is to control the directional movement of cells.We can enhance the therapeutic efficacy of adoptive cellular therapy by screening for appropriate chemokines and chemokine receptors.However,the screened chemokines and chemokine receptors need to meet two conditions:firstly,the chemokines are highly expressed in tumor tissues;secondly,the binding of the chemokines and chemokine receptors is specific and unique.Therefore,firstly,we analyzed the expressional profile of six chemokines that specifically bind to their cognate receptors in human tumor tissues by using data from the "UCSC"website.The results showed that the expression of only one of these six chemokines CCL20,is different between tumor tissues and normal tissues.Then we analyzed the expression of CCL20 in tumor tissues and paracancerous tissues,as well as in tumor cell lines.The results showed that CCL20 was highly expressed on digestive tumor tissues and tumor cells.These results demonstrated that CCL20 can be expressed in parenchymal cells of digestive system tumors.Secondly,we established engeered cells with overexpressing CCR6 including 293T cell,THP1 cell and Jurkat cell and verified that the CCR6-CCL20 chemokine axis can directed the migration of cells in vitro by using Transwell assay.In vivo experiments also demonstrated that the CCR6-CCL20 chemokine axis can directed migration of cells to tumor sites in mouse tumor models.At last,we analysed the influence of the overexpression with CCR6 on the function of the immune cells.we found that the function of immune cells is not affected by the overexpression of CCR6.Instead,it may enhance the antitumor effect of the immune cells since the overexpression of CCR6.The overexpression of CCR6 also promoted expression of the antigen-presenting genes and activation of PI3K/Akt signaling pathway.In summary,in the present study,we demonstrated that the CCR6-CCL20 chemokine axis can mediate the directional migration of immune cells.We also demonstated that CCR6-CCL20 chemokine axis has potentil to solve the problem of randomized direction of the adoptive therapeutic immune cells in the treatment of digestive system carcinomas.Our findings provided a new strategy for improving the efficacy of adoptive cellular therapy for digestive sytem carcinomas,including HCC.