OHSV2 Can Inhibit Colorectal Cancer Liver Metastasis Effectively By Changing The Tumor Microenvironmental Immune Status And Inducing Specific Anti-tumor Immunity

Background:Colon cancer is one of the most clinically common malignant tumors,and the liver is its most common metastatic site,which is the leading cause of death in colon cancer patients.However,the current clinical treatment strategies,including surgery,radiotherapy and chemotherapy,have very limited therapeutic effects in patients with advanced colon cancer,so it is necessary to find more effective and specific treatments to inhibit and attack metastases.Oncolytic virus(OVs)therapy,as a new type of tumor therapy,has the advantages of safety,high efficiency and small side effects.It can selectively infect tumor cells,proliferate and induce lethal damage without harming normal cells.Besides,the process could induce the release of tumor-associated antigens,form a systemic anti-tumor immune response,which could attack the primary tumor and its metastases and then form a persistent immune memory.Purposes:Our preliminary results show that the oncolytic herpes simplex virus oHSV2 with independent intellectual property rights is a safe and effective treatment for mouse 4T1 breast cancer model and CT26 colon cancer animal model.The purpose of this study was to provides a theoretical basis for the treatment of advanced hepatic metastatic of colon cancer with oHSV2 by constructing a mouse hepatic metastatic model of colonic cancer and performing oncolytic virus treatment to observe the direct anti-tumor cytotoxicity of oHSV2,and further study its effect on the tumor microenvironment and the anti-tumor immune resp onse.In this study:firstly,we constructed a mouse model of colon cancer liver metastasis successfully,which was verified by high frequency ultrasound of mouse liver.The rate of liver metastasis was more than 90%.Secondly,after successful modeling,we treated primary axillary lesions with oHSV2,and observed that oHSV2 could not only significantly inhibit the origin of liver metastasis.The growth of CT-26 tumors can significantly reduce the number and size of liver metastases and prolong the median survival time of mice.3.Observed these phenomena,we continued to examine the changes of oHSV2 on tumor microenvironment and immune cells in vivo by immunohistochemistry and flow cytometry,and found that the innate and acquired immunity of mice were activated.After that3 we did not see the growth of CT-26 tumors in mice with successfully cured liver metastases from colon cancer treated with the same tumor cell line(CT-26 colon cancer)for two or three times.But interestingly,when we used the xenogeneic tumor cell line(4T-1 breast cancer)for two times,we observed the slow growth of 4T-1 tumors,which still had statistical difference compared with the control group.Finally,this study concludes that oHSV2 has three killing effects on tumors:one is direct cytotoxicity;the other is to induce systemic innate and acquired immune response,especially specific anti-tumor immune response,which can attack distal and metastatic tumors,kill tumors twice,and form immune memory in the process to produce lasting anti-tumors.Therapeutic effect,prevention of recurrence of tumors,and good safety.Therefore,oHSV2 will have good clinical application prospects.