miR-142-5p regulates tumor cell PD-L1 expression and enhances anti-tumor immunity.

Cancer immunotherapy has many great achievements in recent years. One of the most promising cancer immunotherapies is PD-1/PD-L1 pathway blockade. miRNAs (MicroRNAs) belongs to small noncoding RNA and can regulate gene expression by binding to the 3'UTR. Many miRNAs can inhibit cancer growth by regulating the PD-L1 expression in cancer cells. Herein, we firstly found that PD-L1 could be the target of miR-142-5p by using bioinformatics methods, then we conduct luciferase activity assay, RT-PCR and western blot experiments to demonstrate that miR-142-5p can regulate PD-L1 expression by binding to its 3'UTR. And in vivo experiments certified that miR-142-5p overexpression can inhibit pancreatic cancer growth. Flow cytometry and RT-PCR experiment demonstrated that miR-142-5p overexpression on tumor cells inhibits the expression of PD-L1 on tumor cells which result in the increase of CD4+ T lymphocytes and CD8+ T lymphocytes, the decrease of PD-1+ T lymphocytes and increase of IFN-γ and TNF-α. So, miR-142-5p overexpression can enhance anti-tumor immunity by blocking PD-L1/PD-1 pathway. Our results identify a novel mechanism by which PD-L1 is regulated by miR-142-5p and overexpression of miR-142-5p could enhance the anti-tumor immunity.

Jia L ，Xi Q ，Wang H ，Zhang Z ，Liu H ，Cheng Y ，Guo X ，Zhang J ，Zhang Q ，Zhang L ，Xue Z ，Li Y ，Da Y ，Zhao P ，Zhang R ... -  《-》

miR-194-5p down-regulates tumor cell PD-L1 expression and promotes anti-tumor immunity in pancreatic cancer.

Pancreatic cancer is a highly malignant cancer of the digestive tract. Studies have shown that in some types of cancer, a high level of microRNA-194-5p (miR-194-5p) is beneficial for controlling tumor progression, while in other cancers it plays a completely opposite role. However, how miR-194-5p affects anti-tumor immunity of pancreatic cancer remains unclear. In this study, we found that high expression of miR-194-5p in human pancreatic cancer patients is associated with a better survival rate, while increased expression of programmed cell death ligand 1 (PD-L1) in human pancreatic cancer patients is associated with a worse survival rate. In pancreatic cancer, the expression level of PD-L1 is negatively correlated with the expression level of miR-194-5p, and we identified that PD-L1 was target gene of miR-194-5p. In addition, we found that overexpression of miR-194-5p inhibited the migration, invasion and proliferation of pancreatic cancer cells in vitro. The orthotopic mouse model of pancreatic cancer shown that miR-194-5p suppressed the progression of pancreatic cancer, promoted the infiltration of CD8+ T cells in tumor immune microenvironments, and enhanced the IFN-γ production of CD8+ T cells. Consistently, the co-culture experiments showed that overexpression of miR-194-5p in tumor cell enhanced IFN-γ production by CD8+ T cells. In conclusion, miR-194-5p may serve as a novel immunotherapeutic target for pancreatic ductal adenocarcinoma (PDAC) by inhibiting the expression of PD-L1, and play important roles in inhibiting the progression of pancreatic cancer and boosting the anti-tumor effect of CD8+ T cells.

Wang C ，Li X ，Zhang L ，Chen Y ，Dong R ，Zhang J ，Zhao J ，Guo X ，Yang G ，Li Y ，Gu C ，Xi Q ，Zhang R ... -  《-》

The tumor suppressor miR-138-5p targets PD-L1 in colorectal cancer.

Zhao L ，Yu H ，Yi S ，Peng X ，Su P ，Xiao Z ，Liu R ，Tang A ，Li X ，Liu F ，Shen S ... -  《Oncotarget》

Long noncoding RNA LINC00473 drives the progression of pancreatic cancer via upregulating programmed death-ligand 1 by sponging microRNA-195-5p.

Pancreatic cancer (PC) is a great health burden to patients owing to its poor overall survival rate. Long noncoding RNAs (lncRNAs) interact with microRNAs (miRs) to participate in tumorigenesis. Therefore, we aim to uncover the role and related mechanism of LINC00473 in PC through the modulation of miR-195-5p and programmed death-ligand 1 (PD-L1). Increased LINC00473 and PD-L1 but declined miR-195-5p were determined in PC tissues and cell lines, and it was found that LINC00473 mainly situated in the cytoplasm. Also, miR-195-5p was verified to bind with both LINC00473 and PD-L1. Next, with the aim to examine the ability of LINC00473, miR-195-5p, and PD-L1 on the PC progression, the expression of LINC00473, miR-195-5p and PD-L1 were altered with mimics, inhibitors, overexpression vectors or siRNAs in PC cells and cocultured CD8+ T cells. It was demonstrated that LINC00473 sponged miR-195-5p to upregulate PD-L1 expression. More important, the obtained results revealed that LINC00473 silencing or miR-195-5p upregulation elevated the expression of Bcl-2 associated X protein (Bax), interferon (IFN)-γ, and interleukin (IL)-4 but reduced the expression of B-cell lymphoma-2 (Bcl-2), matrix metalloproteinase (MMP)-2, MMP-9, and IL-10, thus inducing the enhancement of the apoptosis as along with the inhibition of proliferation, invasion, and migration of the PC cells. LINC00473 silencing or miR-195-5p elevation activated the CD8+ T cells. Taken together, LINC00473 silencing blocked the PC progression through enhancing miR-195-5p-targeted downregulation of PD-L1. This finding offers new therapeutic options for treating this devastating disease.

Zhou WY ，Zhang MM ，Liu C ，Kang Y ，Wang JO ，Yang XH ... -  《-》

miR-142-5p regulates CD4+ T cells in human non-small cell lung cancer through PD-L1 expression via the PTEN pathway.

Wan J ，Ling X ，Peng B ，Ding G ... -  《-》