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

Abstract

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.

Identification of key serum biomarkers for the diagnosis and metastatic prediction of osteosarcoma by analysis of immune cell infiltration

“…Each of which has the capacity to regulate M2 macrophages and cancer characteristics [ 33 , 34 ]. Hsa-miR-326 is involved in the regulation of programmed death ligand 1 (PD-L1) and CD8+ T cells [ 35 ]. Transcription factors are important targets for non-coding RNAs.…”

“…Shao et al . reported that hsa-miR-326 regulates the expression of immune checkpoint molecules, PD-L1 and B7-H3, which affect the cytokine profile of CD8+ T cells as well as lung adenocarcinoma cell migration [ 35 ]. PD-L1 and B7-H3 have been identified as targets for immunotherapeutic intervention in OS [ 54 ].…”

lncRNA MANCR Inhibits NK Cell Killing Effect on Lung Adenocarcinoma by Targeting miRNA-30d-5p

“…Numerous studies implied that improving immune function and inhibiting immune escape can inhibit malignant progression of LUAD [34][35][36]. NK cells take a crucial part in the prognosis of tumors because they can induce immune responses after cancer treatment [37].…”

CircFOXK2 enhances tumorigenesis and immune evasion in non–small cell lung cancer by miR-485-5p/PD-L1 axis

“…Moreover, miR-148a overturned cell migration and invasion by Wnt1 in NSCLC [14]. Besides, miR-7-5p subdued tumor metastasis in NSCLC via binding NOVA2 [15]. What's more, Cheng et al demonstrated that miR-485-5p content was reduced in NSCLC [16].…”