The Role Of MiR-214 And MiR-155 In Tumor Immune Escape

Accumulating evidence indicates that a cross-talk between tumors and the immune system can promote immune escape.To modulate the immune system in tumor environment is very important for tumor treatment.The expansion of CD4+CD25+Foxp3+ regulatory T-cells(Tregs)under tumor conditions contributes to the immune evasion by the tumor cells.The mechanism of Treg induction by tumor,however,remains incompletely understood.Here we report that cancer cells can actively suppress the immune function by secreting miR-214-containing microvesicles(MVs),which are delivered into the peripheral CD4+T-cells;this results in a reduction of phosphatase and tensin homolog(PTEN),leading to the polarization of the CD4+T-cells into Tregs.This effect of the tumor cell MVs on the Treg expansion and immune suppression could be abolished by depleting miR-214 in the MVs.Furthermore,the MV delivery of anti-miR-214 antisense oligonucleotides into tumor-implanted mice significantly blocked the tumor-induced expansion of Tregs and decreased the tumor growth.Tumor-associated macrophages(TAMs)are critical regulators of the tumor microenvironment and directly affect multiple steps in tumor development,including the growth,survival,invasion,and metastasis of tumor cells.The molecular mechanisms underlying TAM polarization to different phenotypes are the focus of intense investigation.In this paper,we present evidence that microRNA-155(miR-155)is a key molecule controlling macrophage polarization and that the overexpression of miR-155 can re-program anti-inflammatory,pro-tumorial M2 TAMs to pro-inflammatory,anti-tumor M1 macrophages.First,low-density miRNA microarray and qRT-PCR assays showed that the miR-155 level was strikingly increased when macrophages were polarized to the M1 phenotype,whereas the depletion of miR-155 blocked macrophage M1 polarization.Second,the differential expression of miR-155 was confirmed in different phenotypic macrophages isolated from various pathological conditions.Third,the forced expression of miR-155 switched TAMs to the M1 phenotype.Finally,functional studies showed that miR-155-"modified" TAMs regained tumor-killing capacity.In summary,the present studies demonstrate miRNA-based mechanisms for manipulating immune system.They may prove effective and novel therapeutic approaches for cancer.