The Fuction And Mechanism Of MiR-26a In Tumor-infiltrating CD8~+T Cells

Surgery?chemotherapy?radiotherapy and immunotherapy which become the new hope are all treatments against cancer.As the most important effecor of antitumor immunity,the tumor microenvironment(TME)always limits the potency of CD8+ cytotoxic T lymphocyte(CTL)responses.MicroRNAs(miRNAs)are newly discovered,20~22 nucletides-long,non-coding RNAs with regulatory function and have been shown to play a pivotal role in T cell function.In our study we provided evidence that microRNA-26a(miR-26a)is a negative regulator of CTL function in the TME.Firstly,we analyzed miRNAs expression in CTLs which isolated from the PBMCs and pleural effusion of NSCLC(non-small cell lung carcinoma)patients.It was found that the expression of miR-26 a was significantly upregulated in the CTLs sorted from the pleural effusion compared to the CTLs sorted from the PBMCs,which was negatively correlated with the granzyme B production.Unsurprising,the overexpression of miR-26 a obviously inhibited the secretion of IFN-? and Granzyme B which were CTLs effector molecules.It was confirmed the cytokines in the tumor microenvironment could induce the expression of miR-26 a in CTLs and were closely related to CTL immunosuppressive.As we all know,the mechanism of miRNA on gene expression based on the complementary binding of miRNA to the 3?-UTR sequences of the target genes,and then leading to suppression at the translational and post-transcriptional level.To further study the target gene of miR-26 a.We searched the potential genes by miRecord.Among the target genes,EZH2 was highly conserved for miR-26 a seed region pairing and it was reported involved in CTL function.The double luciferase reporter assay confirmed that EZH2 was the target gene for miR-26 a.Meanwhile,the expression of EZH2 in CD8+ T cells was downregulated in tumor microenvironment,and the function of CTLs was destroied when EZH2 was inhibited.It suggests that miR-26 a impairs CTLs fuction by inhibition of EZH2.This study will be helpful to improve the molecular mechanism of the suppression of CTLs function in tumor microenvironment,and also provides a new target for anti-tumor immune therapy.