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Background: Immunotherapy using immune checkpoint inhibitors (ICIs) is the current focus in cancer immunotherapy. However, issues are raised in the area, as the recent studies showed that such therapeutic modality suffers from low durability and low or no efficacy for patients with some tumor types including cases with non‐inflamed or cold cancers. Therefore, efforts have been made to solve the issue using immune combination therapy, such as the use of immunocytokines. The combination of ICI with interleukins (ILs) and IL‐targeting agents is now under consideration in the area of therapy, and the primary results are promising. Purpose: The focus of this review is to discuss the possibility of using ILs and IL‐targeting drugs in combination with ICI in cancer immunotherapy and describing recent advances in the field using PEGylated ILs and fusion proteins. The key focus in this area is to reduce adverse events and to increase the efficacy and durability of such combination therapy. [ABSTRACT FROM AUTHOR]

• FOXP3 controls Treg differentiation and activity. • FOXP3 induces metabolic versatility in intra-tumoral Tregs. • Treg subsets show different reliance on FOXP3. Dysregulation of regulatory T cells (Tregs) is described in the context of inflammatory and autoimmune diseases, and cancer. Forkhead box P3 (FOXP3) is a transcription factor that its activity is an indicator of Treg identity. FOXP3 induces metabolic versatility in intra-tumoral Tregs, so that its deficiency mediates Treg instability or even gives rise to the acquisition of effector T cell phenotype. FOXP3 dysregulation and defectiveness occurs upon ubiquitination, methylation and presumably acetylation. Stimulators of PTEN, mammalian target of rapamycin complex 2 (mTORC2), and nucleus accumbens–associated protein-1 (NAC1), and inhibitors of B lymphocyte-induced maturation protein-1 (Blimp-1), Deltex1 (DTX1) and ubiquitin-specific peptidase 22 (USP22) are suggested to hamper FOXP3 stability, and to promote its downregulation and further Treg depletion. A point is that Treg subsets reveal different reliance on FOXP3, which indicates that not all Tregs are strictly dependent on FOXP3, and presumably Tregs with different origin rely on diverse regulators of FOXP3 stability. The focus of this review is over the current understanding toward FOXP3, its activity in Tregs and influence from different regulators within tumor microenvironment (TME). Implication of FOXP3 targeting in cancer immunotherapy is another focus of this paper. [ABSTRACT FROM AUTHOR]

Traditionally, vaccines have helped eradication of several infectious diseases and also saved millions of lives in the human history. Those prophylactic vaccines have acted through inducing immune responses against a live attenuated, killed organism or antigenic subunits to protect the recipient against a real infection caused by the pathogenic microorganism. Nevertheless, development of anticancer vaccines as valuable targets in human health has faced challenges and requires further optimizations. Dendritic cells (DCs) are the most potent antigen presenting cells (APCs) that play essential roles in tumor immunotherapies through induction of CD8+ T cell immunity. Accordingly, various strategies have been tested to employ DCs as therapeutic vaccines for exploiting their activity against tumor cells. Application of whole tumor cells or purified/recombinant antigen peptides are the most common approaches for pulsing DCs, which then are injected back into the patients. Although some hopeful results are reported for a number of DC vaccines tested in animal and clinical trials of cancer patients, such approaches are still inefficient and require optimization. Failure of DC vaccination is postulated due to immunosuppressive tumor microenvironment (TME), overexpression of checkpoint proteins, suboptimal avidity of tumor-associated antigen (TAA)-specific T lymphocytes, and lack of appropriate adjuvants. In this review, we have an overview of the current experiments and trials evaluated the anticancer efficacy of DC vaccination as well as focusing on strategies to improve their potential including combination therapy with immune checkpoint inhibitors (ICIs). • DC vaccination is the current focus in cancer therapy. • DC vaccination acts through enhancement of antitumor immune responses. • Clinical efficacy of DC vaccination is not satisfactory. • Combination with ICIs increases antitumor efficacy of DC vaccination. [ABSTRACT FROM AUTHOR]

B7 homolog 3 (B7-H3, also called CD276) is a checkpoint of B7 family that is aberrantly and consistently expressed in several human cancers, and its overexpression correlates with weak prognosis. B7-H3 is expressed on a number of cells, and it acts as a driver of immune evasion. This is mediated through hampering T cell infiltration and promoting exhaustion of CD8+ T cells. Increased B7-H3 activity also promotes macrophage polarity toward pro-tumor type 2 (M2) phenotype. In addition, high B7-H3 activity induces aberrant angiogenesis to promote hypoxia, a result of which is resistance to common immune checkpoint inhibitor (ICI) therapy. This is mediated through the impact of hypoxia on dampening CD8+ T cell recruitment into tumor area. The immunosuppressive property of B7-H3 offers insights into targeting this checkpoint as a desired approach in cancer immunotherapy. B7-H3 can be a target in blocking monoclonal antibodies (mAbs), combination therapies, chimeric antigen receptor-modified T (CAR-T) cells and bispecific antibodies. • B7-H3 is overexpressed in tumor vs. normal tissue. • B7-H3 hampers CD8+ T cell infiltration and promotes their exhaustion. • B7-H3 poorly co-expresses with PD-L1. • B7-H3 can provide an alternative mechanism for bypassing ICI therapy. • Anti-B7-H3 biAbs act more selectively compared with monotherapy. [ABSTRACT FROM AUTHOR]

Extending the durability of response is the current focus in cancer immunotherapy with immune checkpoint inhibitors (ICIs). However, factors like non-immunogenic tumor microenvironment (TME) along with aberrant angiogenesis and dysregulated metabolic systems are negative contributors. Hypoxia is a key TME condition and a critical promoter of tumor hallmarks. It acts on immune and non-immune cells within TME in order for promoting immune evasion and therapy resistance. Extreme hypoxia is a major promoter of resistance to the programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitor therapy. Hypoxia inducible factor-1 (HIF-1) acts as a key mediator of hypoxia and a critical promoter of resistance to the anti-PD-(L)1. Targeting hypoxia or HIF-1 can thus be an effective strategy for reinvigoration of cellular immunity against cancer. Among various strategies presented so far, the key focus is over vascular normalization, which is an approach highly effective for reducing the rate of hypoxia, increasing drug delivery into the tumor area, and boosting the efficacy of anti-PD-(L)1. • Hypoxic TME is a key promoter of ICI resistance/refractory. • High PD-L1 level is a marker of poor prognosis but higher response to ICIs. • Aberrant angiogenesis/hypoxia/dysregulated metabolism promote T cell exclusion/exhaustion. • Vascular normalization dampens tumor hypoxia and promotes ICI sensitization. • Low-dose anti-angiogenic therapy increases ICI sensitivity. [ABSTRACT FROM AUTHOR]

Human endogenous retrovirus H long terminal repeat-associating protein 2 (HHLA2 or B7-H7) is a newly discovered B7 family member. HHLA2 is aberrantly expressed in solid tumors and exerts co-stimulatory or co-inhibitory activities dependent on interaction with counter receptors. HHLA2 represents co-stimulatory effects upon interaction with transmembrane and immunoglobulin domain containing 2 (TMIGD2, also called CD28H), but its interaction with killer cell Ig-like receptor, three Ig domains and long cytoplasmic tail 3 (KIR3DL3) renders co-inhibitory effects. TMIGD2 is mainly expressed on resting or naïve T cells, whereas expression of KIR3DL3 occurs on activated T cells. HHLA2/KIR3DL3 attenuates responses from both innate and adaptive anti-tumor immunity, and the activity within this axis is regarded as a biomarker of weak prognosis in cancer patients. HHLA2/KIR3DL3 promotes CD8+ T cell exhaustion and induces macrophage polarity toward pro-tumor M2 phenotype. HHLA2 represents diverse expression profile and activity in tumor and stroma. Tumoral expression of HHLA2 is presumably higher compared with programmed death-ligand 1 (PD-L1), and HHLA2 co-expression with PD-L1 is indicative of more severe outcomes. A suggested strategy in patients with HHLA2high cancer is to use monoclonal antibodies for specifically suppressing the HHLA2 inhibitory receptor KIR3DL3, not the HHLA2 ligand. TMIGD2 can be a target for development of agonistic bispecific antibodies for hampering tumor resistance to the programmed death-1 (PD-1)/PD-L1 blockade therapy. • HHLA2 elicits stimulatory or inhibitory activities receptor dependently. • HHLA2 regulation reduces innate/adaptive immune responses. • TMIGD2 and KIR3DL3 are expressed on resting and activated T cells, respectively. • HHLA2/KIR3DL3 blockade reinvigorates anti-tumor immunity. • Agonistic TMIGD2 can be a target for developing bispecific antibodies. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitor (ICI) resistance demands for acquisition of novel strategies in order to broaden the therapeutic repertoire of advanced cancers. Bispecific antibodies can be utilized as an emerging therapeutic paradigm and a step forward in cancer immunotherapy. Synchronous inhibition of programmed death-1 (PD-1), programmed death-ligand 1 (PD-L1) or cytotoxic T lymphocyte associated antigen-4 (CTLA-4), or with other agents can expand antibody selectivity and improve therapeutic window through tightening cell-to-cell bridge (a process called immunological synapse) within tumor immune microenvironment (TIME). There is evidence of higher potency of this co-targeting approach over combined single-agent monoclonal antibodies in reinvigorating anti-tumor immune responses, retarding tumor growth, and improving patient survival. In fact, immunological synapses formed by interactions of such bispecific agents with TIME cells directly mediate cytotoxicity against tumor cells, and durable anti-tumor immune responses are predictable after application of such agents. Besides, lower adverse events are reported for bispecific antibodies compared with individual checkpoint inhibitors. These are all indicative of the importance of exploiting novel bispecific approach as a replacement for conventional combo checkpoint inhibitor therapy particularly for tumors with immunosuppressive or cold immunity. Study in this area is still continued, and in the future more will be known about the importance of this bispecific approach in cancer immunotherapy. • Bispecific inhibitors are more effective compared with combination of single-agent mAbs. • Lower adverse events are reported for bispecific (vs. monospecific) antibodies. • Bispecific inhibitors reactivate anti-cancer T cells more selectively. [ABSTRACT FROM AUTHOR]

Resistance to immune checkpoint inhibitors (ICIs) is a major issue of the current era in cancer immunotherapy. Immune evasion is a multi-factorial event, which occurs generally at a base of cold immunity. Despite advances in the field, there are still unsolved challenges about how to combat checkpoint hijacked by tumor cells and what are complementary treatment strategies to render durable anti-tumor outcomes. A point is that anti-programed death-1 receptor (PD-1)/anti-programmed death-ligand 1 (PD-L1) is not the solo path of immune escape, and responses in many types of solid tumors to the PD-1/PD-L1 inhibitors are not satisfactory. Thus, seeking mechanisms inter-connecting tumor with its immune ecosystem nearby unravel more about resistance mechanisms so as to develop methods for sustained reinvigoration of immune activity against cancer. In this review, we aimed to discuss about common and specific paths taken by tumor cells to evade immune surveillance, describing novel detection strategies, as well as suggesting some approaches to recover tumor sensitivity to the anti-PD-(L)1 therapy based on the current knowledge. • Resistance to anti-PD-(L)1 is multi-factorial. • Defective infiltration and effector CD8+ T cells is a critical driver of ICI resistance. • PD-L1 high MHC-I low tumor cell signature is a reliable biomarker of ICI resistance. [ABSTRACT FROM AUTHOR]

Background: Wharton's Jelly-Mesenchymal Stem Cells (WJ-MSCs) are pluripotent cells with differentiation capability into most cell lineages. The aim of the current work was to examine the role of Retinoic Acid (RA) in differentiation process of these cells into hepatocyte-like cells and determine the morphological and functional patterns. Methods: Human WJ-MSCs were extracted, cultured and expanded; after approximately 95% of confluence, the cells were treated with hepatogenic media containing RA. The cells were subsequently analyzed for morphological changes, glycogen storage, albumin production, and specific gene expression. Results: WJ-MSCs expressed high levels of CD90 (93.6%) and CD105 (90.7%), but low levels of CD34 (0.3%) and CD45 (0.8%). Albumin production had significant difference in the two groups (p≤0.05). The data showed specific characteristics in favor of considering the differentiated cells as hepatocyte-like cells such as obtaining morphologic, functional, and αFP and HNF1-α expression patterns which in turn were higher in cells exposed to RA. Conclusion: Based on the data of present study, RA is an effective molecule in inducing differentiation of WJ-MSCs into hepatocyte-like cells; therefore, it may be considered as a promising factor for targeting therapy of liver disorders. [ABSTRACT FROM AUTHOR]

Interleukin-6 (IL-6) is a multi-tasking cytokine that represents high activity in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and cancer. High concentration of this pleiotropic cytokine accounts for hyperinflammation and cytokine storm, and is related to multi-organ failure in patients with SARS-CoV-2 induced disease. IL-6 promotes lymphopenia and increases C-reactive protein (CRP) in such cases. However, blockade of IL-6 is not a full-proof of complete response. Hypoxia, hypoxemia, aberrant angiogenesis and chronic inflammation are inter-related events occurring as a response to the SARS-CoV-2 stimulatory effect on high IL-6 activity. Taking both pro- and anti-inflammatory activities will make complex targeting IL-6 in patient with SARS-CoV-2 induced disease. The aim of this review was to discuss about interactions occurring within the body of patients with SARS-CoV-2 induced disease who are representing high IL-6 levels, and to determine whether IL-6 inhibition therapy is effective for such patients or not. We also address the interactions and targeted therapies in cancer patients who also have SARS-CoV-2 induced disease. • IL-6 is a hallmark of inflammatory feature in severe/critical SARS-CoV-2 induced disease. • CRP level is a predictor of response to IL-6 inhibitor therapy. • The efficacy of tocilizumab is moderate in severe SARS-CoV-2 induced disease. • SARS-CoV-2-induced IL-6 seemingly strengthens cancer aggression. • IL-6 inhibitors can go with ICI in cancer (not in SARS-CoV-2 induced disease). [ABSTRACT FROM AUTHOR]

Radiotherapy is a common modality for more than half of cancer patients. Classically, radiation is known as a strategy to kill cancer cells via direct interaction with DNA or generation of free radicals. Nowadays, we know that modulation of immune system has a key role in the outcome of radiotherapy. Selecting an appropriate dose per fraction is important for stimulation of anti-tumor immunity. Unfortunately, cancer cells and other cells within tumor microenvironment (TME) promote some mechanisms implicated in the attenuation of anti-tumor immunity via exhaustion of CD8 + T lymphocytes and natural killer (NK) cells. Immunotherapy with immune checkpoint inhibitors (ICIs) has shown to be an interesting adjuvant for induction of more effective anti-tumor immunity. Clinical trial studies are ongoing for uncovering more knowledge about the efficacy of ICI combination with radiotherapy. Some newer pre-clinical studies show more effective therapeutic window for targeting PD-1 and some other targets in combination with hypofractionated radiotherapy. In this review, we explain cellular and molecular consequences in the TME following radiotherapy and promising immune targets to enhance anti-tumor immunity. [ABSTRACT FROM AUTHOR]

Nanotechnology is a growing science that may provide several new applications for medicine, food preservation, diagnostic technologies, and sanitation. Despite its beneficial applications, there are several questions related to the safety of nanomaterials for human use. The development of nanotechnology is associated with some concerns because of the increased risk of carcinogenesis following exposure to nanomaterials. The increased levels of reactive oxygen species (ROS) that are due to exposure to nanoparticles (NPs) are primarily responsible for the genotoxicity of metal NPs. Not all, but most metal NPs are able to directly produce free radicals through the release of metal ions and through interactions with water molecules. Furthermore, the increased production of free radicals and the cell death caused by metal NPs can stimulate reduction/oxidation (redox) reactions, leading to the continuous endogenous production of ROS in a positive feedback loop. The overexpression of inflammatory mediators, such as NF-kB and STATs, the mitochondrial malfunction and the increased intracellular calcium levels mediate the chronic oxidative stress that occurs after exposure to metal NPs. In this paper, we review the genotoxicity of different types of metal NPs and the redox mechanisms that amplify the toxicity of these NPs. Image 1 • MNPs can increase the risk of mutagenesis and carcinogenesis causing cell death. • MNPs are able to produce ROS and free radicals through the direct/indirect integrations. • The overexpression of inflammatory mediators by MNPs can mediates the chronic oxidative stress. • ROS generation and oxidative stress induced by MNPs can lead to genotoxicity and cell death. • MNP's composition, size, shape, and surface coating determine the genotoxicity. [ABSTRACT FROM AUTHOR]

Background: Colon tumor is generated and maintained by a small subset of chemo-resistant cancer cells known as Cancer Stem-like Cells (CSCs) that are able to self-renew and differentiate into various cell types within the cancer milieu. CSCs are identified through expression of CD133 that is the most important surface marker of these cells. Epithelial Cell Adhesion Molecule (EpCAM) is another colon CSCs marker. Other markers that are probably involved in colon tumorigenesis are Leucine-rich repeat- containing G-protein-coupled Receptor 5 (LGR5), B cell-specific Moloney murine leukemia virus insertion site 1 (BMI1) and Ten-Eleven Translocations (TETs). Methods: Here, mRNA expression rates of LGR5, BMI1 and TETs were surveyed by real-time PCR. After collection and digestion, colon samples were used to isolate CD133 and EpCAM positive CSCs through evaluation of AC133 EpCAM by Magnetic Activated Cell Sorting (MACS) and flow cytometry. Real-time PCR was carried out for assessing expressions of LGR5, BMI1 and TETs. Results: High expressions for LGR5, BMI1, TET1 and TET2 in the CD133 and EpCAM positive CSCs (p≤0.05 vs. non-CSCs) were found. TET3, however, showed no significant changes for mRNA expression in the CSCs. Conclusion: In conclusion, high mRNA expressions for LGR5, BMI1, TET1 and TET2 in the CD133 and EpCAM positive CSCs may be a useful criterion for better identification of the cells involved in colon cancer in order to specify therapeutic targets against this type of cancer. [ABSTRACT FROM AUTHOR]

Immunotherapy has revolutionized treatment of cancer during the last decades. Oncolytic virotherapy has also emerged as a strategy to fight against cancer cells both via lysis of malignant cells and activating immune responses. Accepted as a logical strategy, combination of monoclonal antibodies particularly against the programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) is introduced to improve clinical responses to immune checkpoint inhibitors (ICIs). Accordingly, Talimogene laherparepvec (T-VEC) has received approval for clinical use, while a number of oncolytic Adenoviruses (Ads) are being investigated in clinical trials of malignancies. Combination of oncolytic Ads with PD-1/PD-L1 inhibitors have shown potentials in promoting responses to ICIs, changing the tumor microenvironment, inducing long-term protection against tumor, and promoting survival among mice models of malignancies. Regarding the increasing importance of oncolytic Ads in combination therapy of cancers, in this review we decide to outline recent studies in this field. [ABSTRACT FROM AUTHOR]

Background: Many autocrine and paracrine elements that are produced within follicular niche have been the focus of much in vitro maturation (IVM) research. The present study was carried out to compare retinoic acid (RA) and basic fibroblast growth factor (bFGF) efficacy on IVM of mouse oocytes, and their further dual consumption to reach an optimal protocol. Materials and Methods: In this experimental study, germinal vesicle (GV) oocytes obtained from two-months-old NMRI mice were randomly divided into control, sham and three experimental groups. The basic culture medium was α-MEM supplemented with 10% fetal bovine serum (FBS), 50 mg/l streptomycin, 60 mg/l penicillin and 10 ng/ml epidermal growth factors. Each of the experimental groups received one of the following treatments: RA (2 µM), bFGF (20 ng/ml) or combination of RA and bFGF with the indicated concentrations. After 24 hours, capacitated spermatozoa were added to in vitro matured oocytes. Five hours later, the oocytes were cultured in fresh droplets of M2 medium for 24 hours and assessed for cleavage to the two-cells stage. Results: As compared with the control group, the rate of maturation was significantly increased in the RA (P<0.001) and bFGF+RA (P<0.02) groups with 58 ± 10 and 57 ± 3.46, respectively. The rate of maturation was significant in the RA (P<0.02) and bFGF+RA (P<0.03) groups, in comparison with the bFGF group. The bFGF+RA group had higher rate (83 ± 1.52) of two-cells development, than control (33 ± 1, P<0.001). Conclusion: Our findings showed beneficial effects of 2 µM RA and 20 ng/ml bFGF combination on mouse oocyte IVM. [ABSTRACT FROM AUTHOR]