A Systematic Review on the Therapeutic Potentiality of PD-L1-Inhibiting MicroRNAs for Triple-Negative Breast Cancer: Toward Single-Cell Sequencing-Guided Biomimetic Delivery

Abstract

The programmed death-ligand 1 (PD-L1)/programmed cell death protein 1 (PD-1) is a well-established inhibitory immune checkpoint axis in triple-negative breast cancer (TNBC). Growing evidence indicates that tumoral PD-L1 can lead to TNBC development. Although conventional immune checkpoint inhibitors have improved TNBC patients’ prognosis, their effect is mainly focused on improving anti-tumoral immune responses without substantially regulating oncogenic signaling pathways in tumoral cells. Moreover, the conventional immune checkpoint inhibitors cannot impede the de novo expression of oncoproteins, like PD-L1, in tumoral cells. Accumulating evidence has indicated that the restoration of specific microRNAs (miRs) can downregulate tumoral PD-L1 and inhibit TNBC development. Since miRs can target multiple mRNAs, miR-based gene therapy can be an appealing approach to inhibit the de novo expression of oncoproteins, like PD-L1, restore anti-tumoral immune responses, and regulate various intracellular singling pathways in TNBC. Therefore, we conducted the current systematic review based on the preferred reporting items for systematic reviews and meta-analyses (PRISMA) to provide a comprehensive and unbiased synthesis of currently available evidence regarding the effect of PD-L1-inhibiting miRs restoration on TNBC development and tumor microenvironment. For this purpose, we systematically searched the Cochrane Library, Embase, Scopus, PubMed, ProQuest, Web of Science, Ovid, and IranDoc databases to obtain the relevant peer-reviewed studies published before 25 May 2021. Based on the current evidence, the restoration of miR-424-5p, miR-138-5p, miR-570-3p, miR-200c-3p, miR-383-5p, miR-34a-5p, miR-3609, miR-195-5p, and miR-497-5p can inhibit tumoral PD-L1 expression, transform immunosuppressive tumor microenvironment into the pro-inflammatory tumor microenvironment, inhibit tumor proliferation, suppress tumor migration, enhance chemosensitivity of tumoral cells, stimulate tumor apoptosis, arrest cell cycle, repress the clonogenicity of tumoral cells, and regulate various oncogenic signaling pathways in TNBC cells. Concerning the biocompatibility of biomimetic carriers and the valuable insights provided by the single-cell sequencing technologies, single-cell sequencing-guided biomimetic delivery of these PD-L1-inhibiting miRs can decrease the toxicity of traditional approaches, increase the specificity of miR-delivery, enhance the efficacy of miR delivery, and provide the affected patients with personalized cancer therapy.

A Systematic Review on PD-1 Blockade and PD-1 Gene-Editing of CAR-T Cells for Glioma Therapy: From Deciphering to Personalized Medicine

“…In this regard, single-cell sequencing of tumor bulk can help identify (potential) patient-specific neoantigens. Single-cell sequencing technologies can provide valuable insights into the expression profile of tumoral cells and categorize tumoral cells based on their neoantigens ( 15 , 51 ). Therefore, this categorization can allow us to develop personalized CAR-T cells with different molecular targets for each patient.…”

“…For our included in vivo studies, we utilized the “SYRCLE’s RoB” tool, adapted from the Cochrane RoB tool ( 13 ). For our included in vitro studies, we adapted the previously used quality assessment tool ( 14 , 15 ).…”

Blood Circulating Non-Coding RNAs for the Clinical Management of Triple-Negative Breast Cancer

“…ncRNAs regulating the PD-1/PD-L1 axis are able to change the sensitivity of cells toward pembrolizumab. For instance, miRNA-34a, 138, 200c, 424, and 570, let-7a, and lncRNAs CCAT1 and GATA3-AS1 can regulate tumor growth and proliferation through PD-L1 modulation, and thus response to immunotherapy [98][99][100]. In a clinical trial (KEYNOTE-086), Loi et al, using RNA-seq-based data, confirmed that inflammatory state signatures obtained by measuring the tissue-resident memory are asso-ciated with the response to pembrolizumab in TNBC patients [101].…”

A Systematic Review and Meta-Analysis on the Significance of TIGIT in Solid Cancers: Dual TIGIT/PD-1 Blockade to Overcome Immune-Resistance in Solid Cancers

“…Moreover, TIGIT blockade can improve the efficacy of anti-PD-1 therapy and promote the stimulation of tumor-infiltrating CD8 + T-cells in patients with bladder cancer [ 42 ]. Besides, TIGIT/PD-1 dual blockade has remarkably improved anti-tumoral immune responses and promoted tumor rejection in lymphoma animal models [ 10 ]. Furthermore, the dual blockade of the immune checkpoint axes of PD-1 and TIGIT has been superior in rejecting melanoma and non-small-cell lung carcinoma [ 43 , 44 ].…”

“…This axis can be established between immune and tumor cells and can substantially contribute to immunosuppressive tumor microenvironment development [8]. Although monoclonal antibodies targeting this inhibitory axis have been promising for some solid cancers, like triple-negative breast cancer, they have not yielded meaningful results in other solid cancers, like glioblastoma [9,10]. The low response rate of some patients to anti-PD-1 might be stemmed from the fact that other inhibitory immune checkpoint molecules can also regulate anti-tumoral immune responses.…”