MicroRNA-326 attenuates immune escape and prevents metastasis in lung adenocarcinoma by targeting PD-L1 and B7-H3

Shao，Lijuan1,2,3; He，Qian1,2; Wang，Jingbo1,2,3; He，Fei1,2; Lin，Shengcheng4; Wu，Liujing1,2; Gao，Yubiao1,2; Ma，Wei1,2; Dong，Jun3; Yang，Xiaofei1,2,3; Li，Furong1,2,3

2021-06-01

10.1038/s41420-021-00527-8

Cell Death Discovery   影响因子和分区

2058-7716

Tumor-infiltrating T cells are highly expressive of inhibitory receptor/immune checkpoint molecules that bind to ligand expressed by tumor cells and antigen-presenting cells, and eventually lead to T cell dysfunction. It is a hot topic to restore T cell function by targeting immune checkpoint. In recent years, immunotherapy of blocking immune checkpoint and its receptor, such as PD-L1/PD-1 targeted therapy, has made effective progress, which brings hope for patients with advanced malignant tumor. However, only a few patients benefit from directly targeting these checkpoints or their receptors by small compounds or antibodies. Since the complexity of the regulation of immune checkpoints in tumor cells, further research is needed to identify the novel endogenous regulators of immune checkpoints which can help for developing effective drug target to improve the effect of immunotherapy. Here, we verified that microRNA-326 (miR-326) repressed the gene expression of immune checkpoint molecules PD-L1 and B7-H3 in lung adenocarcinoma (LUAD). We detected that the expression of miR-326 in LUAD tissue was negatively correlated with PD-L1/B7-H3. The repression of PD-L1 and B7-H3 expression through miR-326 overexpression leads to the modification the cytokine profile of CD8 T cells and decreased migration capability of tumor cells. Meanwhile, the downregulation of miR-326 promoted tumor cell migration. Moreover, blocking PD-L1 and B7-H3 attenuated the tumor-promoting effect induced by miR-326 inhibitor. In tumor-bearing mice, the infiltration of CD8 T cells was significantly increased and the expression of TNF-α, and IFN-γ was significantly enhanced which contributed to tumor progression after miR-326 overexpression. Collectively, miR-326 restrained tumor progression by downregulating PD-L1 and B7-H3 expression and increasing T cell cytotoxic function in LUAD. Our findings revealed a novel perspective on the complex regulation of immune checkpoint molecules. A new strategy of using miR-326 in tumor immunotherapy is proposed.

英语

第一 ; 通讯

2-s2.0-85108180390

Scopus

1.Translational Medicine Collaborative Innovation Center,Shenzhen People’s Hospital (The Second Clinical Medical College,Jinan University; The First Affifiliated Hospital,Southern University of Science and Technology),Shenzhen,518020,China
2.Shenzhen key laboratory of stem cell research and clinical transformation,Shenzhen,518020,China
3.Integrated Chinese and Western Medicine Postdoctoral Research Station,Jinan University,Guangzhou,510632,China
4.National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital,Chinese Academy of Medical Sciences and PeKing Union Medical College,Shenzhen,518116,China

Shao，Lijuan,He，Qian,Wang，Jingbo,et al. MicroRNA-326 attenuates immune escape and prevents metastasis in lung adenocarcinoma by targeting PD-L1 and B7-H3[J]. Cell Death Discovery,2021,7(1).

Shao，Lijuan.,He，Qian.,Wang，Jingbo.,He，Fei.,Lin，Shengcheng.,...&Li，Furong.(2021).MicroRNA-326 attenuates immune escape and prevents metastasis in lung adenocarcinoma by targeting PD-L1 and B7-H3.Cell Death Discovery,7(1).

Shao，Lijuan,et al."MicroRNA-326 attenuates immune escape and prevents metastasis in lung adenocarcinoma by targeting PD-L1 and B7-H3".Cell Death Discovery 7.1(2021).