p53 downregulates PD-L1 expression via miR-34a to inhibit the growth of triple-negative breast cancer cells: a potential clinical immunotherapeutic target

Abstract

Compared with other breast cancer subtypes, triple-negative breast cancer (TNBC) has poorer responses to therapy and lower overall survival rates. The use of an inhibitor of immune checkpoint programmed cell death ligand 1 (PD-L1) is a promising treatment strategy and is approved for malignant tumors, especially for TNBC. p53 regulates various biological processes, but the association between p53 and immune evasion remains unknown. miR-34a is a known tumor suppressor and p53-regulated miRNA that is downregulated in several cancers; however, it has not been reported in TNBC. Herein, we aimed to explore the regulatory signaling axis among p53, miR-34a and PD-L1 in TNBC cells in vivo and in tissue and to improve our understanding of immunotherapy for TNBC. p53-EGFP, p53-siRNA and miR-34a mimics were transfected into TNBC cell lines, and the interaction between miR-34a and PD-L1 was analyzed via dual-luciferase reporter assays. We found that p53 could inhibit the expression of PD-L1 via miR-34a and that miR-34a could inhibit both cell activity and migration and promoted apoptosis and cytotoxicity in TNBC. Furthermore, miR-34a agomir was injected into MDA-MB-231 tumors of nude mice. The results showed that miR-34a could inhibit tumor growth and downregulate the expression of PD-L1 in vivo. A total of 133 TNBC tissue samples were analyzed by immunochemistry; the proportion of positive expression of PD-L1 was 57.14% (76/133), and the proportion of samples with negative expression of PD-L1 was 42.86% (57/133). Our research may provide a novel potential target for TNBC.

MicroRNAs as regulators of immune checkpoints in cancer immunotherapy: targeting PD-1/PD-L1 and CTLA-4 pathways

“…Moreover, the findings indicated that miR-34a can suppress the growth of tumors and reduce the levels of PD-L1 in TNBC [ 164 ].…”

MicroRNA-34 Family in Cancers: Role, Mechanism, and Therapeutic Potential

“…The inhibition of programmed cell death-ligand 1 (PD-L1), an immune checkpoint, has emerged as a promising treatment strategy. It has been shown that the tumor suppressor protein p53 can downregulate PD-L1 expression through miR-34a, thereby inhibiting the growth of TNBC cells [78]. Circulating miR-34 family expression levels could serve as noninvasive prognostic biomarkers in TNBC patients.…”

Exploring the Potential Role of Circulating microRNAs as Biomarkers for Predicting Clinical Response to Neoadjuvant Therapy in Breast Cancer

“…miR-140-5p inhibits proliferation of BCSC and increases doxorubicin efficacy by targeting Wnt1, a crucial regulator of the Wnt/β-catenin pathway [ 93 ]. Recently, Deng et al [ 94 ] noticed that miR-34a could inhibit tumor growth, cell activity, and migration and can promote cytotoxicity and apoptosis in TNBC through PD-L1 and p53; and miR-98-5p regulates cell proliferation, invasion, and migration by targeting IGF1 in BC tissues [ 95 ]. Hence, differential miRNA expression during BC treatment can provide a novel tool for better understanding how anticancer drugs act alone and in combination, allowing treatment optimization [ 56 ].…”