The prognostic and therapeutic potential of HO-1 in leukemia and MDS.

BACKGROUND: Heme oxygenase-1 (HO-1), a heme-degrading enzyme, is proven to have anti-apoptotic effects in several malignancies. In addition, HO-1 is reported to cause chemoresistance and increase cell survival. Growing evidence indicates that HO-1 contributes to the course of hematological malignancies as well. Here, the expression pattern, prognostic value, and the effect of HO-1 targeting in HMs are discussed. MAIN BODY: According to the recent literature, it was discovered that HO-1 is overexpressed in myelodysplastic syndromes (MDS), chronic myeloid leukemia (CML), acute myeloblastic leukemia (AML), and acute lymphoblastic leukemia (ALL) cells and is associated with high-risk disease. Furthermore, in addition to HO-1 expression by leukemic and MDS cells, CML, AML, and ALL leukemic stem cells express this protein as well, making it a potential target for eliminating minimal residual disease (MRD). Moreover, it was concluded that HO-1 induces tumor progression and prevents apoptosis through various pathways. CONCLUSION: HO-1 has great potential in determining the prognosis of leukemia and MDS patients. HO-1 induces resistance to several chemotherapeutic agents as well as tyrosine kinase inhibitors and following its inhibition, chemo-sensitivity increases. Moreover, the exact role of HO-1 in Chronic Lymphocytic Leukemia (CLL) is yet unknown. While findings illustrate that MDS and other leukemic patients could benefit from HO-1 targeting. Future studies can help broaden our knowledge regarding the role of HO-1 in MDS and leukemia. Video abstract.

Targeting the CTLA-4/B7 axes in glioblastoma: preclinical evidence and clinical interventions.

INTRODUCTION: Glioblastoma Multiforme (GBM) is one of the fatal cancers of the Central Nervous System (CNS). A variety of reasons exist for why previous immunotherapy strategies, especially Immune Checkpoint Blockers (ICBs), did not work in treating GBM patients. The cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is a key immune checkpoint receptor. Its overexpression in cancer and immune cells causes tumor cell progression. CTLA-4 suppresses anti-tumor responses inside the GBM tumor-immune microenvironment. AREAS COVERED: It has been attempted to explain the immunobiology of CTLA-4 as well as its interaction with different immune cells and cancer cells that lead to GBM progression. Additionally, CTLA-4 targeting studies have been reviewed and CTLA-4 combination therapy, as a promising therapeutic target and strategy for GBM immunotherapy, is recommended. EXPERT OPINION: CTLA-4 could be a possible supplement for future cancer immunotherapies of GBM. However, many challenges remain such as the high toxicity of CTLA-4 blockers, and the unresponsiveness of most patients to immunotherapy. For the future clinical success of CTLA-4 blocker therapy, combination approaches with other targeted treatments would be a potentially effective strategy. Going forward, predictive biomarkers can be used to reduce trial timelines and increase the chance of success.

Novel, First-in-Human, Oral PCLX-001 Treatment in a Patient with Relapsed Diffuse Large B-Cell Lymphoma.

Patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) have limited treatment options, particularly if they are transplantation or chimeric antigen receptor (CAR) T-cell ineligible, and novel therapeutics are needed. An 86-year-old woman with relapsed DLBCL received a novel, first-in-class small molecule inhibitor of N-myristoyltransferase (NMT) as the initial patient on a phase I dose escalation trial. Daily oral administration of 20 mg PCLX-001 tablets produced a pharmacokinetic profile suitable for single daily dosing: rapid oral absorption, followed by an apparent elimination half-life of 16 h, without systemic accumulation of drug by day 15. Pharmacodynamic tests showed no clear change in NMT1 and NMT2 levels or selected NMT substrate Lyn and HGAL protein levels in normal circulating blood mononuclear cells, suggesting a higher dose will be required for normal tissue toxicity. The patient did not experience any dose-limiting toxicities but had disease progression after 28 days of study therapy. Dose escalation continues in other patients in this first-in-human study of a new class of anticancer drug. We conclude that PCLX-001 oral monotherapy has suitable pharmacokinetic parameters for dose escalation, and that higher doses are required to achieve pharmacodynamic evidence of on-target activity in normal tissues. The current protocol is appropriately designed to achieve these ends, and the study proceeds without modification.

Anti-tumor immunity in mismatch repair-deficient colorectal cancers requires type I IFN-driven CCL5 and CXCL10.

Colorectal cancers (CRCs) deficient in DNA mismatch repair (dMMR) contain abundant CD8+ tumor-infiltrating lymphocytes (TILs) responding to the abundant neoantigens from their unstable genomes. Priming of such tumor-targeted TILs first requires recruitment of CD8+ T cells into the tumors, implying that this is an essential prerequisite of successful dMMR anti-tumor immunity. We have discovered that selective recruitment and activation of systemic CD8+ T cells into dMMR CRCs strictly depend on overexpression of CCL5 and CXCL10 due to endogenous activation of cGAS/STING and type I IFN signaling by damaged DNA. TIL infiltration into orthotopic dMMR CRCs is neoantigen-independent and followed by induction of a resident memory-like phenotype key to the anti-tumor response. CCL5 and CXCL10 could be up-regulated by common chemotherapies in all CRCs, indicating that facilitating CD8+ T cell recruitment underlies their efficacy. Induction of CCL5 and CXCL10 thus represents a tractable therapeutic strategy to induce TIL recruitment into CRCs, where local priming can be maximized even in neoantigen-poor CRCs.

Combined inhibition of CD73 and ZEB1 by Arg-Gly-Asp (RGD)-targeted nanoparticles inhibits tumor growth.

Abnormal expression of several macromolecules within tumor milieu helps the development of neoplasia and immune suppression in various cancers. ZEB-1 and CD73 are important factors in tumor progression, which their overexpression in tumor site enhances several cancer hallmarks, including proliferation, angiogenesis, metastasis, migration, and invasion. In this study, we decided to inhibit the expression of these factors in the tumor site by using RGD-conjugated chitosan lactate (RGD-CL) nanoparticles (NPs) encapsulating CD73/ZEB-1 siRNA molecules, in vitro and in vivo. The NPs were about 127 nm in size, non-toxic, and RGD conjugation to NPs could efficiently increase cell transfection through interaction with αvß3 integrins expressed on cancer cells and tumoral endothelial cells.Moreover, RGD-conjugated CL NPs containing siRNAs could significantly reduce the ZEB-1 and CD73 expression levels in cancer cells. Following transfection, cancer cells showed a significant reduction in migration and proliferation. Furthermore, the administration of these NPs into 4T1 and CT26 tumor-bearing mice resulted in tumor suppression and prolonged survival. These findings indicate the importance of targeting the CD73/ZEB1 axis in cancer cells, which could encourage their use in cancer patients in the near future.

EP4 receptor as a novel promising therapeutic target in colon cancer.

The most prevalent malignancy that can occur in the gastrointestinal tract is colon cancer. The current treatment options for colon cancer patients include chemotherapy, surgery, radiotherapy, immunotherapy, and targeted therapy. Although the chance of curing the disease in the early stages is high, there is no cure for almost all patients with advanced and metastatic disease. It has been found that over-activation of cyclooxygenase 2 (COX-2), followed by the production of prostaglandin E2 (PGE2) in patients with colon cancer are significantly increased. The tumorigenic function of COX-2 is mainly due to its role in the production of PGE2. PGE2, as a main generated prostanoid, has an essential role in growth and survival of colon cancer cell's. PGE2 exerts various effects in colon cancer cells including enhanced expansion, angiogenesis, survival, invasion, and migration. The signaling of PGE2 via the EP4 receptor has been shown to induce colon tumorigenesis. Moreover, the expression levels of the EP4 receptor significantly affect tumor growth and development. Overexpression of EP4 by various mechanisms increases survival and tumor vasculature in colon cancer cells. It seems that the pathway starting with COX2, continuing with PGE2, and ending with EP4 can promote the spread and growth of colon cancer. Therefore, targeting the COX-2/PGE2/EP4 axis can be considered as a worthy therapeutic approach to treat colon cancer. In this review, we have examined the role and different mechanisms that the EP4 receptor is involved in the development of colon cancer.

Codelivery of HIF-1α siRNA and Dinaciclib by Carboxylated Graphene Oxide-Trimethyl Chitosan-Hyaluronate Nanoparticles Significantly Suppresses Cancer Cell Progression.

PURPOSE: Hypoxia-inducible factor (HIF) is one of the critical components of the tumor microenvironment that is involved in tumor development. HIF-1α functionally and physically interacts with CDK1, 2, and 5 and stimulates the cell cycle progression and Cyclin-Dependent Kinase (CDK) expression. Therefore, hypoxic tumor microenvironment and CDK overexpression lead to increased cell cycle progression and tumor expansion. Therefore, we decided to suppress cancer cell expansion by blocking HIF-1α and CDK molecules. METHODS: In the present study, we used the carboxylated graphene oxide (CGO) conjugated with trimethyl chitosan (TMC) and hyaluronate (HA) nanoparticles (NPs) loaded with HIF-1α-siRNA and Dinaciclib, the CDK inhibitor, for silencing HIF-1α and blockade of CDKs in CD44-expressing cancer cells and evaluated the impact of combination therapy on proliferation, metastasis, apoptosis, and tumor growth. RESULTS: The results indicated that the manufactured NPs had conceivable physicochemical properties, high cellular uptake, and low toxicity. Moreover, combination therapy of cancer cells using CGO-TMC-HA NPs loaded with HIF-1α siRNA and Dinaciclib (SCH 727965) significantly suppressed the CDKs/HIF-1α and consequently, decreased the proliferation, migration, angiogenesis, and colony formation in tumor cells. CONCLUSIONS: These results indicate the ability of CGO-TMC-HA NPs for dual drug/gene delivery in cancer treatment. Furthermore, the simultaneous inhibition of CDKs/HIF-1α can be considered as a novel anti-cancer treatment strategy; however, further research is needed to confirm this treatment in vivo. Graphical Abstract The suppression of HIF-1α and CDKs inhibits cancer growth. HIF-1α is overexpressed by the cells present in the tumor microenvironment. The hypoxic environment elevates mitochondrial ROS production and increases p38 MAP kinase, JAK/STAT, ERK, JNK, and Akt/PI3K signaling, resulting in cyclin accumulation and aberrant cell cycle progression. Furthermore, the overexpression of HIF-1α/CDK results in increased expression of genes such as BCL2, Bcl-xl, Ki-67, TGFß, VEGF, FGF, MMP2, MMP9, and, HIF-1α and consequently raise the survival, proliferation, angiogenesis, metastasis, and invasion of tumor cells. In conclusion, HIF-1α-siRNA/Dinaciclib-loaded CGO-TMC-HA NPs can inhibit the tumor expansion by blockage of CDKs and HIF-1α (JAK: Janus kinase, STAT: Signal transducer and activator of transcription, MAPK: mitogen-activated protein kinase, ERK: extracellular signal-regulated kinase, JNK: c-Jun N-terminal kinase, PI3K: phosphatidylinositol 3-kinase).

Inhibition of CD73 using folate targeted nanoparticles carrying anti-CD73 siRNA potentiates anticancer efficacy of Dinaciclib.

Conventional therapeutic methods against cancer, including chemotherapy, radiotherapy, surgery, and combination therapy, have exhibited different toxicity levels due to their unspecific mechanism of action. To overcome the challenges facing conventional cancer therapies, newly developed methods are being investigated. Significant levels of specificity, remarkable accumulation at the tumor site, limited side effects, and minimal off-target effects enable the newly synthesized nanoparticles (NPs) to become the preferred drug delivery method in anticancer therapeutic approaches. According to the literature, CD73 has a pivotal role in cancer progression and resistance to chemotherapy and radiotherapy. Therefore, CD73 has attracted considerable attention among scientists to target this molecule. Accordingly, FDA approved CDK inhibitors such as Dinaciclib that blocks CDK1, 2, 5, and 9, and exhibits significant anticancer activity. So in this study, we intended to simultaneously suppress CD73 and CDKs in cancer cells by using the folic acid (FA)-conjugated chitosan-lactate (CL) NPs loaded with anti-CD73 siRNA and Dinaciclib to control tumor progression and metastasis. The results showed that NPs could effectively transfect cancer cells in a FA receptor-dependent manner leading to suppression of proliferation, survival, migration, and metastatic potential. Moreover, the treatment of tumor-bearing mice with this combination strategy robustly inhibited tumor growth and enhanced survival time in mice. These findings imply the high potential of FA-CL NPs loaded with anti-CD73 siRNA and Dinaciclib for use in cancer treatment shortly.

Blockade of CTLA-4 increases anti-tumor response inducing potential of dendritic cell vaccine.

The immunosuppressive state of the tumor microenvironment diminishes the efficacy of dendritic cell (DC)-based cancer immunotherapy. Inhibitory immune checkpoint molecules expressed on tumor-infiltrating T lymphocytes, such as cytotoxic T-lymphocyte antigen 4 (CTLA-4) molecules are one of the main barriers in priming T cells by DCs. Therefore, it seems that blockade of such molecules facilitates the T cells activation by the DC vaccine. In this study, we intended to suppress the expression of CTLA-4 molecule on tumor-infiltrating T cells by siRNA-loaded chitosan-lactate (CL) nanoparticles to facilitate priming anti- tumor T cells by tumor lysate-loaded DC vaccine. Nanoparticles (NPs) have also provided an opportunity for specific drug delivery into the tumor site. CL NPs exhibited favorable physicochemical characteristics (size about 75 nm, polydispersive index<0.2, and a zeta potential about 14), which were associated with a high transfection rate and low toxicity. Moreover, the administration of anti-CTLA-4 siRNA-loaded NPs into CT26 and 4 T1 tumor -bearing mice led to the downregulation of CTLA-4 on tumor -infiltrating T cells, which was associated with tumor regression and increased mice survival. Moreover, while the treatment of tumor -bearing mice with DC vaccine had mild therapeutic outcomes, its combination with siRNA-loaded NPs may exhibit synergistic anti- tumor effects. This possible synergistic ameliorating effect is achieved through the reduction of immunosuppressive cells, the improved cytotoxicity of T lymphocytes, decreased inhibitory and increased inflammatory cytokines, and reduced angiogenesis and metastasis processes. These results indicate that the silencing of CTLA-4 can potentiate the T cell priming capacity of the DC vaccine, proposing a practical anti-cancer therapeutic approach.

Concomitant blockade of A2AR and CTLA-4 by siRNA-loaded polyethylene glycol-chitosan-alginate nanoparticles synergistically enhances antitumor T-cell responses.

Inhibitory immune checkpoint (ICP) molecules are important immunosuppressive factors in a tumor microenvironment (TME). They can robustly suppress T-cell-mediated antitumor immune responses leading to cancer progression. Among the checkpoint molecules, cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) is one of the critical inhibitors of anticancer T-cell responses. Besides, the expression of adenosine receptor (A2AR) on tumor-infiltrating T cells potently reduces their function. We hypothesized that concomitant silencing of these molecules in T cells might lead to enhanced antitumor responses. To examine this assumption, we purified T cells from the tumor, spleen, and local lymph nodes of CT26 colon cancer-bearing mice and suppressed the expression of A2AR and CTLA-4 using the small interfering RNA (siRNA)-loaded polyethylene glycol-chitosan-alginate (PCA) nanoparticles. The appropriate physicochemical properties of the produced nanoparticles (NPs; size of 72 nm, polydispersive index [PDI] < 0.2, and zeta potential of 11 mV) resulted in their high efficiency in transfection and suppression of target gene expression. Following the silencing of checkpoint molecules, various T-cell functions, including proliferation, apoptosis, cytokine secretion, differentiation, and cytotoxicity were analyzed, ex vivo. The results showed that the generated nanoparticles had optimal physicochemical characteristics and significantly suppressed the expression of target molecules in T cells. Moreover, a concomitant blockade of A2AR and CTLA-4 in T cells could synergistically enhance antitumor responses through the downregulation of PKA, SHP2, and PP2Aα signaling pathways. Therefore, this combination therapy can be considered as a novel promising anticancer therapeutic strategy, which should be further investigated in subsequent studies.

Silencing of HIF-1α/CD73 axis by siRNA-loaded TAT-chitosan-spion nanoparticles robustly blocks cancer cell progression.

Induction of Hypoxia Inducible Factor (HIF) as a direct consequence of oxygen deficiency in tumor tissues is a potent stimulus of CD73 (ecto-5'-nucleotidase) expression. Hypoxic environment and CD73 overexpression are associated with altered metabolism, elevated cancer cell proliferation, and tumor vascularization. Herein, a delivery system was developed for silencing CD73 and HIF-1α gene using siRNA-loaded Superparamagnetic iron oxide (SPION) nanocarriers for cancer treatment. SPIONs were encapsulated with thiolated chitosan (TC) and trimethyl chitosan (TMC) for improving their stabilization and functionalization. The nanoparticles (NPs) were about 133 nm in size, spherical, and non-toxic, and the addition of TAT peptide (derived from HIV-1 TAT protein) to TMC-TC-SPIONs significantly increased their cellular uptake by cancer cells. The produced NPs could efficiently accumulate in the tumor site, indicating their stability and targeting ability in reaching the tumor region. TAT-conjugated TMC-TC-SPIONs containing siRNAs could significantly reduce the HIF-1α and CD73 expression levels in cancer cells. Following transfection, cancer cells showed a significant reduction in migration and proliferation. Moreover, siRNA-loaded NPs could effectively reduce tumor growth and angiogenesis, as investigated by the chick chorioallantoic membrane (CAM) assay. This study suggested that TAT-TMC-TC-SPIONs can be potential nanocarrier for gene transfection in cancer therapy. Moreover, the co-silencing of CD73 and HIF-1α can be assumed as a novel anti-cancer treatment strategy with high tumor suppression potential.

Silencing adenosine A2a receptor enhances dendritic cell-based cancer immunotherapy.

Overexpression of adenosine in the tumor region leads to suppression of various immune cells, particularly T cells through ligation with adenosine 2a receptor (A2aR). In this study, we intended to increase the efficacy of tumor lysate-loaded DC vaccine by silencing the expression of A2aR on T cells through the application of A2aR-specific siRNA-loaded PEG-chitosan-lactate (PCL) nanoparticles (NPs) in the 4T1 breast tumor-bearing mice. Combination therapy by DC vaccine and siRNA-loaded NPs markedly induced tumor regression and increased survival time of mice. These ameliorative effects were partly via downregulation of immunosuppressive cells, increased function of cytotoxic T lymphocytes, and induction of immune-stimulatory cytokines. Moreover, combination therapy could markedly suppress angiogenesis and metastasis processes. These results imply the efficacy of novel combination therapy for the treatment of breast cancer by using A2aR siRNA-loaded NPs and DC vaccine which can be translated into the initial phase of clinical trials in the near future.

Coinhibition of S1PR1 and GP130 by siRNA-loaded alginate-conjugated trimethyl chitosan nanoparticles robustly blocks development of cancer cells.

There is an interconnected network between S1P/sphingosine-1-phosphate receptor 1 (S1PR1), IL-6/glycoprotein 130 (GP130), and signal transducer and activator of transcription 3 (STAT3) signaling pathways in the tumor microenvironment, which leads to cancer progression. S1P/S1PR1 and IL-6/GP130 signaling pathways phosphorylate and activate STAT3, and it then induces the expression of S1PR1 and interleukin-6 (IL-6) in a positive feedback loop leading to cancer progression. We hypothesized that blockade of this amplification loop can suppress the growth and development of cancer cells. Therefore, we silenced STAT3 upstream molecules including the S1PR1 and GP130 molecules in cancer cells using small interfering RNA (siRNA)-loaded alginate-conjugated trimethyl chitosan (ATMC) nanoparticles (NPs). The generated NPs had competent properties including the appropriate size, zeta potential, polydispersity index, morphology, high uptake of siRNA, high rate of capacity, high stability, and low toxicity. We evaluated the effects of siRNA loaded ATMC NPs on tumor hallmarks of three murine-derived cancer cell lines, including 4T1 (breast cancer), B16-F10 (melanoma), and CT26 (colon cancer). The results confirmed the tumor-suppressive effects of combinational targeting of S1PR1 and GP130. Moreover, combination therapy could potently suppress tumor growth as assessed by the chick chorioallantoic membrane assay. In this study, we targeted this positive feedback loop for the first time and applied this novel combination therapy, which provides a promising approach for cancer treatment. The development of a potent nanocarrier system with ATMC for this combination was also another aspect of this study, which should be further investigated in cancer animal models in further studies.

Differential expression of interferon-lambda receptor 1 splice variants determines the magnitude of the antiviral response induced by interferon-lambda 3 in human immune cells.

Type III interferons (IFN-lambdas(λ)) are important cytokines that inhibit viruses and modulate immune responses by acting through a unique IFN-λR1/IL-10RB heterodimeric receptor. Until now, the primary antiviral function of IFN-λs has been proposed to be at anatomical barrier sites. Here, we examine the regulation of IFN-λR1 expression and measure the downstream effects of IFN-λ3 stimulation in primary human blood immune cells, compared with lung or liver epithelial cells. IFN-λ3 directly bound and upregulated IFN-stimulated gene (ISG) expression in freshly purified human B cells and CD8+ T cells, but not monocytes, neutrophils, natural killer cells, and CD4+ T cells. Despite similar IFNLR1 transcript levels in B cells and lung epithelial cells, lung epithelial cells bound more IFN-λ3, which resulted in a 50-fold greater ISG induction when compared to B cells. The reduced response of B cells could be explained by higher expression of the soluble variant of IFN-λR1 (sIFN-λR1), which significantly reduced ISG induction when added with IFN-λ3 to peripheral blood mononuclear cells or liver epithelial cells. T-cell receptor stimulation potently, and specifically, upregulated membrane-bound IFNLR1 expression in CD4+ T cells, leading to greater antiviral gene induction, and inhibition of human immunodeficiency virus type 1 infection. Collectively, our data demonstrate IFN-λ3 directly interacts with the human adaptive immune system, unlike what has been previously shown in published mouse models, and that type III IFNs could be potentially utilized to suppress both mucosal and blood-borne viral infections.

Nanomedicine for improvement of dendritic cell-based cancer immunotherapy.

Dendritic cell (DC)-based cancer immunotherapy has shown impressive outcomes, including the development of the first FDA-approved anti-cancer vaccine. However, the clinical application of DC-based cancer immunotherapy is associated with various challenges. Promising novel tools for the administration of cancer vaccines has emerged from recent developments in nanoscale biomaterials. One current strategy to enhance targeted drug delivery, while minimizing drug-related toxicities, is the use of nanoparticles (NPs). These can be utilized for antigen delivery into DCs, which have been shown to provide potent T cell-stimulating effects. Therefore, NP delivery represents one promising approach for creating an effective and stable immune response without toxic side effects. The current review surveys cancer immunotherapy with particular attention toward NP-based delivery methods that target DCs.

CDK1 in Breast Cancer: Implications for Theranostic Potential.

Breast cancer has been identified as one of the main cancer-related deaths among women during some last decades. Recent advances in the introduction of novel potent anti-cancer therapeutics in association with early detection methods led to a decrease in the mortality rate of breast cancer. However, the scenario of breast cancer is yet going on and further improvements in the current anti-cancer therapeutic approaches are needed. Several factors are present in the tumor microenvironment which help to cancer progression and suppression of anti-tumor responses. Targeting these cancer-promoting factors in the tumor microenvironment has been suggested as a potent immunotherapeutic approach for cancer therapy. Among the various tumorsupporting factors, Cyclin-Dependent Kinases (CDKs) are proposed as a novel promising target for cancer therapy. These factors in association with cyclins play a key role in cell cycle progression. Dysregulation of CDKs which leads to increased cell proliferation has been identified in various cancers, such as breast cancer. Accordingly, the development and use of CDK-inhibitors have been associated with encouraging results in the treatment of breast cancer. However, it is unknown that the inhibition of which CDK is the most effective strategy for breast cancer therapy. Since the selective blockage of CDK1 alone or in combination with other therapeutics has been associated with potent anti-cancer outcomes, it is suggested that CDK1 may be considered as the best CDK target for breast cancer therapy. In this review, we will discuss the role of CDK1 in breast cancer progression and treatment.

Blockage of immune checkpoint molecules increases T-cell priming potential of dendritic cell vaccine.

Dendritic cell (DC) -based cancer immunotherapy is one of the most important anti-cancer immunotherapies, and has been associated with variable efficiencies in different cancer types. It is well-known that tumor microenvironment plays a key role in the efficacy of various immunotherapies such as DC vaccine. Accordingly, the expression of programmed death ligand 1 (PD-L1) on DCs, which interacts with PD-1 on T cells, leads to inhibition of anti-tumor responses following presentation of tumor antigens by DCs to T cells. Therefore, we hypothesized that down-regulation of PD-L1 in DCs in association with silencing of PD-1 on T cells may lead to the enhancement of T-cell priming by DCs to have efficient anti-tumor T-cell responses. In this study, we silenced the expression of PD-L1 in DCs and programmed cell death protein 1 (PD-1) in T cells by small interfering RNA (siRNA) -loaded chitosan-dextran sulfate nanoparticles (NPs) and evaluated the DC phenotypic and functional characteristics and T-cell functions following tumor antigen recognition on DCs, ex vivo. Our results showed that synthesized NPs had good physicochemical characteristics (size 77·5 nm and zeta potential of 14·3) that were associated with efficient cellular uptake and target gene silencing. Moreover, PD-L1 silencing was associated with stimulatory characteristics of DCs. On the other hand, presentation of tumor antigens by PD-L1-negative DCs to PD-1-silenced T cells led to induction of potent T-cell responses. Our findings imply that PD-L1-silenced DCs can be considered as a potent immunotherapeutic approach in combination with PD-1-siRNA loaded NPs, however; further in vivo investigation is required in animal models.

Regulatory T cells in breast cancer as a potent anti-cancer therapeutic target.

Despite marked advances in treatment approaches, breast cancer is still going to be more prevalent, worldwide. High levels of regulatory T (Treg) cells have repeatedly been demonstrated in circulation, lymph nodes, and tumor samples from patients with various cancer types. The transcription factor Forkhead box protein 3 (Foxp3)-expressing Treg cells have the high suppressive potential of the immune system and are fundamental in preserving immune homeostasis and self-tolerance. However, they enhance tumor development by curbing efficient anti-tumor immune mechanisms in malignancies. Moreover, the accumulation of Treg cells in breast tumors is related to the short overall survival of patients. Treg cell frequency has been applied as an independent predicting factor to diagnose patients with a high risk of relapse. Pulling out all populations of Treg cells to promote the efficacy of anticancer treatment methods may potentially lead to hazardous autoimmune disorders. Thus, realizing the exact structure of tumor-infiltrating Treg cells is pivotal to efficiently target Treg cells in tumors. There are exclusive and non-exclusive approaches to lower down and degrade the number/function of Treg cells. These approaches can include inhibiting tumoral migration, depletion, interference with function, and utilizing T cell plasticity. This review article attempts to clarify the implications concerning the involvement of Treg cells in breast cancer progression and discuss the current approaches in the treatment of this cancer via modulation of Treg cells function.