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The outbreak of coronavirus disease 2019 (COVID-19) has posed a serious threat to public health. There is an urgent need for discovery methods for the prevention and treatment of COVID-19 infection. Understanding immunogenicity together with immune responses are expected to provide further information about this virus. We hope that this narrative review article may create new insights for researchers to take great strides toward designing vaccines and novel therapies in the near future. The functional properties of the immune system in COVID-19 infection is not exactly clarified yet. This is compounded by the many gaps in our understanding of the SARS-CoV-2 immunogenicity properties. Possible immune responses according to current literature are discussed as the first line of defense and acquired immunity. Here, we focus on proposed modern preventive immunotherapy methods in COVID-19 infection.

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.

Triple-negative breast cancer (TNBC) is an invasive tumor with a high incidence of distant metastasis and poor prognosis. In TNBC cells, high PD-L1 expression can induce an immunosuppressive tumor microenvironment, repressing the anti-tumoral immune responses. Although FDA-approved agents targeting the PD-1/PD-L1 axis are potent to eliminate tumoral cells, their immune-related adverse events have become worrisome. As the regulator of gene expression, siRNAs can directly target PD-L1 in breast cancer cells. The gene modification of tumoral PD-L1 can reduce our reliance on the current method of targeting the PD-L1/PD-1 axis. We initiated the study with bioinformatics analysis; the results indicated that TNBC and the MDA-MB-231 cells significantly overexpressed PD-L1 compared to other breast cancer subtypes and cell lines. Our results demonstrated that PD-L1 silencing substantially reduced PD-L1 expression at mRNA and protein levels in MDA-MB-231 cells. Moreover, our results demonstrated that PD-L1 knockdown reduced cancer cell proliferation and induced apoptosis via intrinsic and extrinsic apoptosis pathways. We observed that PD-L1 silencing effectively inhibited the migration of TNBC cells. Further investigation also displayed that silencing of PD-L1 in breast cancer cells induced T-cell cytotoxic function by upregulating the gene expression of pro-inflammatory cytokines, i.e., IL-2, IFN-γ, and TNF-α, and downregulating the gene expression of anti-inflammatory cytokines, i.e., IL-10, and TGF-β, in a co-culture system.

Mesenchymal stem cells (MSCs) are multipotent stromal cells that can differentiate into a variety of cell types. They control the process of hematopoiesis by secreting regulatory cytokines and growth factors and by the expression of important cell adhesion molecules for cell-to-cell interactions. This investigation was intended to examine the effect of bone marrow (BM)-derived MSCs on the differentiation of HL-60 cells according to morphological evaluation, flow cytometry analysis, and gene expression profile.The BM-MSCs were cultured in Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum (FBS). After the third passage, the BM-MSCs were irradiated at 30 Gy. To compare how the HL-60 cells differentiated in groups treated differently, HL-60 cells were cultured in RPMI-1640 and supplemented with 10% FBS. The HL-60 cells were seeded into six-well culture plates and treated with all-trans-retinoic acid (ATRA), BM-MSCs, or BM-MSCs in combination with ATRA, while one well remained as untreated HL-60 cells. The expression levels of the granulocyte subset-specific genes in the HL-60 cells were assayed by real-time polymerase chain reaction.Our results revealed that BM-MSCs support the granulocytic differentiation of the human promyelocytic leukemia cell line HL-60.Based on the results of this study, we concluded that BM-MSCs may be an effective resource in reducing or even preventing ATRA's side effects and may promote differentiation for short medication periods. Though BM-MSCs are effective resources, more complementary studies are necessary to improve this differentiation mechanism in clinical cases.Amaç: Mezankimal kök hücreler (MKH) birçok hücre tipine göre farklılaşabilen multipotent stromal hücrelerdir. Hematopoez sürecini düzenleyici sitokinler ve büyüme faktörleri salınımı ile ve hücreler arası etkileşim için önemli hücresel adezyon moleküllerinin ifadesi yoluyla kontrol ederler. Bu çalışma da kemik iliği (Kİ) kaynaklı MKH HL-60 hücrelerinin farklılaşması üzerine etkisini morfolojik değerlendirme, akım sitometri ve gen ifade analizi yöntemleriyle araştırılması amaçlanmıştır. Gereç ve Yöntemler: Kİ-MKH %10 fetal sığır serumu (FSS) içeren Dulbecco’nun modifiye Eagle ortamında kültür edildi. Üçüncü pasaj sonrası, Kİ-MKH 30 Gy ile ışınlandı. HL-60 hücrelerinin farklı şartlarda nasıl farklılaştığını karşılaştırmak için HL-60 hücreler %10 FSS eklenmiş RPMI-1640 ortamında kültür edildi. HL-60 hücreleri altı kuyucuklu plaklarda all-trans retinoik asit (ATRA), Kİ-MKH ve ATRA ile birlikte Kİ-MKH ile muamele edilirken, bir kuyucuğa sadece HL-60 hücreleri kondu. HL-60 hücrelerinde granülosit alt gruplarına özgü genlerin ifade düzeyleri gerçek zamanlı polimeraz zincir reaksiyonu ile değerlendirildi. Bulgular: Sonuçlarımız Kİ-MKH’nin insan promiyelositik lösemi hücre dizisi HL-60’ın granülositik farklılaşmasını desteklediğini gösterdi. Sonuç: Bu çalışmanın bulgularına göre, Kİ-MKH’nin ATRA yan etkilerini azaltıcı ve hatta önleyici etkili bir kaynak olduğu ve kısa ilaç kullanımı süreçlerinde farklılaşmayı uyarabileceği sonucunu çıkarttık. Kİ-MKH etkili bir kaynak olsa da, klinik olgularda bu farklılaşma mekanizmasını iyileştirmek için destekleyici ek çalışmalara ihtiyaç vardır.

Mitogen-activated protein kinase (MAPK) signal transduction, as a highly conserved signaling pathway, is reported to be involved in various biological events, including metabolic reprogramming, cell proliferation, survival, and differentiation. Mutations in key molecules involved in MAPK/ERK signaling and dysregulation of this pathway are very common events in various human malignancies, which make the MAPK signaling a crucial signaling pathway participating in the regulation of glucose uptake by malignant cells and tumorigenesis. MicroRNAs (miRNAs), as small non-coding RNAs, are critical regulators of gene expression that play key roles in cancer initiation and progression. On the other hand, these small RNAs mutually regulate the MAPK signaling which is often overexpressed in the case of cancer progression; suggesting that crosstalk between miRNAs and this signaling pathway plays a pivotal role in the development of human cancers. Some miRNAs such as miR-20b, miR-34c-3p, miR-152, miR-181a, and miR-302b through inhibiting MAPK signaling, and miR-193a-3p, miR-330-3p, and miR-592 by activating this signaling pathway, play imperative roles in tumorigenesis. Therefore, in this review, we aimed to focus on the interplay between miRNAs and MAPK signaling in the various steps of tumorigenesis, including metabolic regulation, cell proliferation, apoptosis, metastasis, angiogenesis, and drug resistance. Mitogen-activated protein kinase (MAPK) signal transduction, as a highly conserved signaling pathway, is reported to be involved in various biological events, including metabolic reprogramming, cell proliferation, survival, and differentiation. Mutations in key molecules involved in MAPK/ERK signaling and dysregulation of this pathway are very common events in various human malignancies, which make the MAPK signaling a crucial signaling pathway participating in the regulation of glucose uptake by malignant cells and tumorigenesis. MicroRNAs (miRNAs), as small non-coding RNAs, are critical regulators of gene expression that play key roles in cancer initiation and progression. On the other hand, these small RNAs mutually regulate the MAPK signaling which is often overexpressed in the case of cancer progression; suggesting that crosstalk between miRNAs and this signaling pathway plays a pivotal role in the development of human cancers. Some miRNAs such as miR-20b, miR-34c-3p, miR-152, miR-181a, and miR-302b through inhibiting MAPK signaling, and miR-193a-3p, miR-330-3p, and miR-592 by activating this signaling pathway, play imperative roles in tumorigenesis. Therefore, in this review, we aimed to focus on the interplay between miRNAs and MAPK signaling in the various steps of tumorigenesis, including metabolic regulation, cell proliferation, apoptosis, metastasis, angiogenesis, and drug resistance.

Antioxidants are essential in preventing the formation and suppressing the activities of reactive nitrogen and oxygen species. The aim of this study was to review the role of antioxidants in cancer development or prevention. Antioxidants are believed to prevent and treat various types of malignancies. Currently, natural antioxidant compounds have been generally consumed to prevent and treat cancers. Certainly, phenolic compounds extracted from medicinal plants have opened a new prospect with respect to the prevention and treatment of cancers due to having antioxidant characteristics. However, some recently published studies have revealed that antioxidant compounds do not indicate absolute anti-tumor properties. Some antioxidants are helpful in cancer initiation and progression. Taken together, antioxidants demonstrate a two-faced nature toward cancer. However, it is required to conduct further cell culture and in vivo studies to confirm the exact role of antioxidants and then use them for efficient cancer treatments.

Triple-negative breast cancer (TNBC) is heterogeneous cancer with poor prognosis among the other breast tumors. Rapid recurrence and increased progression rate could be reasons for the poor prognosis of this type of breast cancer. Recently, because of the lack of specific targets in multiple cancer treatment, immune checkpoint blockade therapies with targeting PD-1/PD-L1 axis have displayed significant advances and improved survival. Among different types of breast cancers, TNBC is considered more immunogenic with high T-cell and other immune cells infiltration compared to other breast cancer subtypes. This immunogenic characteristic of TNBC is a beneficial marker in the immunotherapy of these tumors. Clinical studies with a focus on immune checkpoint therapy have demonstrated promising results in TNBC treatment. In this review, we summarize clinical trials with the immunotherapy-based treatment of different cancers and also discuss the interaction between infiltrating immune cells and breast tumor microenvironment. In addition, we focus on the signaling pathway that controls PD-L1 expression and continues with CAR T-cell therapy and siRNA as novel strategies and potential tools in targeted therapy.

This meta-analysis aimed to evaluate the prognostic value of tumor-infiltrating lymphocytes (TILs) and programmed death-ligand 1 (PD-L1), their associations with the clinicopathological characteristics, and the association between their levels in patients with triple-negative breast cancer (TNBC). PubMed, EMBASE, Scopus, ProQuest, Web of Science, and Cochrane Library databases were searched to obtain the relevant papers. Seven studies with 1152 patients were included in this study. Like the level of TILs, there were no significant associations between PD-L1 expression and tumor size, tumor stage, lymph node metastasis, histological grade, and Ki67 (All p-values ≥ 0.05). Furthermore, there was no significant association between PD-L1 expression with overall survival (OS) and disease-free survival (DFS). In assessment of TILs and survival relationship, the results showed that a high level of TILs was associated with long-term OS (hazard ratios (HR) = 0.48, 95% CI: 0.30 to 0.77, p-value < 0.001) and DFS (HR = 0.53, 95% CI: 0.35 to 0.78, p-value < 0.001). The results displayed that tumoral PD-L1 expression was strongly associated with high levels of TILs in TNBC patients (OR = 8.34, 95% CI: 2.68 to 25.95, p-value < 0.001). In conclusion, the study has shown the prognostic value of TILs and a strong association between tumoral PD-L1 overexpression with TILs in TNBC patients.