Study On BRAF^V600E Mutation And Immune Microenvironment Characteristics And Clinical Significance In Papillary Thyroid Carcinoma

Objective:The overall mortality rate of papillary thyroid carcinoma（PTC）is low,but it is highly prone to recurrence and metastasis,which greatly affects the prognosis of patients.BRAF ^V600Eis a common mutated gene in PTC,and its mutation is closely related to the poor clinical outcomes of patients,but the mechanism under it remains to be elucidated.Tumors have complex internal heterogeneity,in which disruption of immune microenvironment homeostasis can cause imbalance of endogenous host immune surveillance and promote tumor immune escape,thus allowing tumors to acquire higher aggressiveness and ultimately trigger poor prognosis.The aim of this study is to explore the relationship between BRAF ^V600Emutation and immunomodulatory molecules and infiltrating immune cells in PTC,so as to summarize what kind of tumor immune microenvironment characteristics exist in PTC with or without mutations of BRAF ^V600E,and to provide new directions and ideas for the corresponding mechanism research.Methods:We detected the expression of BRAF ^V600E,PD-L1,PD-1,VISTA and CD3,CD8,Fox P3 in 120 cases of PTC tissue microarray by immunohistochemistry,and analyzed the relationship between the expression of BRAF ^V600Eand the infiltration of immunomodulatory molecules and tumor infiltrating immune cells.Meanwhile,the correlation between BRAF ^V600Eand the clinicopathological and immunological characteristics of PTC was analyzed based on the TCGA database.Results:The mutation rate of BRAF ^V600Ewas 61/108（56.5%）and 59.1%in TCGA database,showing a good consistency.Patients with BRAF ^V600Emutations expressed higher levels of PD-L1（88.5%vs.44.7%）and VISTA（75.4%vs.53.4%）than BRAF ^WT（wild-type）patients.On the contrary,the expression of PD-1（14.8%vs.21.3%）was higher in BRAF ^WTtumors.Although high CD8 expression is more common in BRAF ^WTspecimens,the difference is not significant.Furthermore,the expression of CD3 and Fox P3 was not significantly different between BRAF ^V600Eand BRAF ^WTtumors.Analysis based on TCGA data showed no significant difference in the expression of PD-1,VISTA and CD8in BRAF ^V600Eand BRAF ^WTtumors,and the mean rank of PD-L1,Fox P3 and CD3expression was higher in the BRAF ^V600Egroup than in the BRAF ^WTgroup,with statistically significant differences（P<0.05）.Furthermore,when both PD-L1 and Fox P3levels were low in BRAF ^V600Egroup,patients had longer overall survival and better prognosis.Although BRAF ^V600Emutation was independent of age and gender of patients,it was associated with TNM stage,which was consistent with the pathological analysis provided by tissue microarray,and was also associated with tumor recurrence/progression,extrathyroidal extension and histological type（P<0.05）.Conclusion:PTC patients with BRAF ^V600Emutations had suppressed immune status in the tumor microenvironment,which leads to the destruction of host immune monitoring function and thus affects the prognosis of patients.By analyzing the potential relationships between BRAF ^V600Eand immunomodulatory molecules and infiltrate immune cells,we may be able to provide a new direction for the study of the corresponding mechanisms as well as to explore new targets and provide a theoretical basis for the targeted treatment of BRAF^V600EPTC tumors.