阻断DKK1通过促进CD4+T细胞Th1型极化改善抗肿瘤免疫应答OA北大核心CSTPCD

Objective:To explore the effect of Dickkopf-1(DKK1)expression on CD4+T cell polarization in malignant tumors and its potential value as a target for cancer immunotherapy.Methods:Bioinformatics algorithm was used to analyze the expression of DKK1 in multiple types of tumor tissues and adjacent tissues,and the correlation between the expression of DKK1 and the prognosis of cancer patients and immune infiltration of tumor microenvironment.The effect of DKK1 protein on the phenotype of CD4+T cells was analyzed by flow cytometry in vitro.A melanoma B16F10 cell mouse subcutaneous transplantation tumor model was established to observe the effects of blocking DKK1 on the growth of mouse transplantation tumor and immune cell infiltration and phenotype in transplantation tumor tissues.Results:The mRNA expression levels of DKK1 in many kinds of tumor tissues were significantly higher than those in adjacent tissues.High expression of DKK1 was related to the poor prognosis of most tumor patients.In most types of tumors DKK1 played important negative regulatory role in CD4+T cell anti-tumor immune response(P<0.05 or P<0.01).The results of flow cytometry in vitro showed that DKK1 protein stimulation significantly decreased the expression levels of T-bet,IFN-γ and CD107a in CD4+T cells(all P<0.01).In the mouse subcutaneous melanoma model,it was found that blocking DKK1 could significantly inhibit the growth of transplanted tumors(P<0.01)and effectively improve the anti-tumor immune responses including the proportion of Th1 cells(T-bet+CD4+)increasing significantly(P<0.001),the proportion of effector CD8+T cells(CD44+CD62L-)increasing significantly(P<0.01),and the proportion of Th2 cells(GATA3+CD4+)and Treg cells decreasing significantly(both P<0.01).Conclusion:Blocking DKK1 can effectively promote the phenotypic polarization of CD4+T cells to Th1.DKK1 has potential value as a target for tumor immunotherapy.