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Lymphocyte activation gene-3 (Lag-3, also called CD223) is an immune checkpoint and a cell surface molecule that is overexpressed in several solid cancer types and promotes tolerance to self and tumor-related antigens. Lag-3 evaluation in tumor samples can be served as a prognostic biomarker in cancer. This checkpoint is expressed preferentially on tumor-infiltrating lymphocytes (TILs), and its overexpression negatively regulates their effector activity and augments the release of immunosuppressive cytokines into the tumor area. Lag-3 positively and extensively correlates with programmed death-1 (PD-1) expression on TILs, and their combined expression promote CD4+ and CD8+ T cell exhaustion and apoptosis. Exhausted T cells expressing Lag-3 are resistant to anti-PD-(L)1, so Lag-3 can be a desired target in dual anti-checkpoint therapy. Targeting Lag-3 represents more power to modify the immune backbone of tumor, and its clinical efficacy is more potent compared with anti-PD-(L)1 therapy. Combo anti-Lag-3/anti-PD-1 can abrogate tolerance among cells of immune system, restore T cell effector function and boost anti-tumor immune responses against cancer in a way more pronounced compared with solo anti-Lag-3 or anti-PD-(L)1, and is particularly effective in anti-PD-(L)1 naïve patients. An advance in the field is the development of bispecific antibodies against Lag-3 and PD-(L)1 with a synergistic impact on T cell activation higher than that for combo anti-Lag-3/anti-PD-(L)1. Studies still need to be continued to grasp more knowledge about the precise role of Lag-3 and its targeting in some cancer types including tumors of gastroesophageal area that show most of the controversies among different studies. • Lag-3 is preferentially expressed on tumor-infiltrating lymphocytes (TILs). • Lag-3 co-expresses with programmed death-1 (PD-1) to promote T cell exhaustion. • Clinical efficacy of anti-Lag-3 is higher compared with anti-PD-(L)1. • Anti-PD-(L)1 naïve patients are more responsive to combo anti-Lag-3/anti-PD-1. • A preferred strategy is to use bispecific (vs. combo) anti-Lag-3/anti-PD-(L)1. [ABSTRACT FROM AUTHOR]

Dysregulation of WNT/β-catenin is a hallmark of many cancer types and a key mediator of metastasis in solid tumors. Overactive β-catenin signaling hampers dendritic cell (DC) recruitment, promotes CD8+ T cell exclusion and increases the population of regulatory T cells (Tregs). The activity of WNT/β-catenin also induces the expression of programmed death-ligand 1 (PD-L1) on tumor cells and promotes programmed death-1 (PD-1) upregulation. Increased activity of WNT/β-catenin signaling after anti-PD-1 therapy is indicative of a possible implication of this signaling in bypassing immune checkpoint inhibitor (ICI) therapy. This review is aimed at giving a comprehensive overview of the WNT/β-catenin regulatory roles on PD-1/PD-L1 axis in tumor immune ecosystem, discussing about key mechanistic events contributed to the WNT/β-catenin-mediated bypass of ICI therapy, and representing inhibitors of this signaling as promising combinatory regimen to go with anti-PD-(L)1 in cancer immunotherapy. Ideas presented in this review imply the synergistic efficacy of such combination therapy in rendering durable anti-tumor immunity. [ABSTRACT FROM AUTHOR]

Metabolic reprogramming is a hallmark of solid cancers. Macrophages as major constituents of immune system take important roles in regulation of tumorigenesis. Pro-tumor M2 macrophages preferentially use oxidative phosphorylation (OXPHOS) to meet their metabolic demands, while anti-tumor M1 macrophages use glycolysis as their dominant metabolic source. Dysregulation in metabolic systems is a driving force of skewing macrophages from M1 toward M2 phenotypical state. Hyperactive M1 macrophages, for instance, release metabolic products that are contributed to M2 macrophage polarization. Thus, metabolic remodeling through reinstating normalization in metabolic systems can be an effective tool in cancer therapy. The key focus of this review is over metabolic systems in macrophages and factors influencing their metabolic acquisition and reprogramming in cancer, as well as discussing bout strategies to adjust macrophage metabolism and reeducation toward M1-like phenotype. M1 and M2 macrophages evolve diverse metabolic priorities. Strike for utilizing TME metabolic sources hampers M1 macrophage polarization. Hyperactive M1 macrophages skew TME macrophages toward M2 phenotype. Shifting TAM metabolism more into glycolysis is important therapeutically. Transient HIF-1low condition favors M1 phenotypical acquisition, whereas consistent HIF-1/lactate high favors M2 polarization. Tumor-associated macrophages (TAMs) are one of the most frequent immune cells infiltrated into tumor area. The cells have intense cross taking with other cells of tumor stroma. The presence of immunosuppressive tumor microenvironment (TME) is contributed to the higher and more potent interactions between M2 macrophages. Metabolic abnormality is a tumor hallmark. Tumor cells harness metabolic byproducts in order for taking a control over immune cells. Enhanced mitochondrial oxidative phosphorylation is a promoter of pro-tumor M2 macrophage polarization, whereas enhanced glycolysis is a promoter of anti-tumor M1 polarization. Lack of sufficient O2 and nutrient sources in stroma of solid tumors account for a shift in tumor cell metabolism toward glycolysis, which is indicative of limited energy sources for macrophages to take glycolysis and polarizing toward M1 phenotype. Besides, hyperactive M1 macrophages due to displaying high glycolytic activity and the subsequent release of high lactate into the TME will lead to the highly acidified TME which subsequently causes deviation in phenotype profiling of macrophages and skewing them toward pro-tumor phenotype. Vascular maturation or normalization will adjust O2 and nutrient conditions in the TME and is a key contributor to the M1 predilection. Exploiting such strategy is not in bias with the predilection glycolysis route for M1 polarization. Instead, when nutrients are available in the tumor ecosystem, metabolic sources are not taken from M1 and other anti-tumor cells of immune system, so they will be more active for acting against tumor cells and dampening their activities. [ABSTRACT FROM AUTHOR]

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]

Macrophages are the most abundant and one of the most critical cells of tumor immunity. They provide a bridge between innate and adaptive immunity through releasing cytokines into the tumor microenvironment (TME). A number of interleukin (IL) cytokine family members is involved in shaping the final phenotype of macrophages toward either a classically-activated pro-inflammatory M1 state with anti-tumor activity or an alternatively-activated anti-inflammatory M2 state with pro-tumor activity. Shaping TME macrophages toward the M1 phenotype or recovering this phenotypic state may offer a promising therapeutic approach in patients with cancer. Here, we focus on the impact of macrophage-polarizing ILs on immune cells and IL-mediated cellular cross-interactions within the TME. The key aim of this review is to define therapeutic schedules for addressing ILs in cancer immunotherapy based on their multi-directional impacts in such a milieu. Gathering more knowledge on this area is also important for defining adverse effects related to cytokine therapy and addressing them for reinforcing the efficacy of immunotherapy against cancer. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor-modified T (CAR-T) are genetically engineered cells to express tumor-specific antigens revolutionizing the treatment of hematologic malignancies. The hostile tumor microenvironment (TME) remains a challenge for CAR-T cell therapy in solid tumors. As a solution, combinational therapy with immune checkpoint inhibitors (ICIs) is shown to improve the safety and efficacy of CAR-T cell therapy. To avoid side effects related to the application of ICIs in combinational therapy, engineering CARs to express tumor-specific antigens may help improvement of clinical outcomes. Those CARs expressing single chain variable fragments (scFvs) or nanobodies against immune checkpoint stimulatory or inhibitory molecules, such as the programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) signaling axis are being extensively studied in various clinical trials. In this review, we discuss the significance of anti-PD-(L)1 scFv-expressing CAR-T cells in the treatment of human cancers, describing current challenges and potential strategies to overcome such predicaments in the area of cancer immunotherapy. [Display omitted] • CAR-T can be a strategy for revolutionizing ICI efficacy. • Anti-PD-(L)1-expressing CAR-T shows equal or better efficacy vs. separate combinational therapy. • Anti-PD-(L)1-expressing CAR-T minimizes toxicities related to systemic ICI application. [ABSTRACT FROM AUTHOR]

Evolution of tumor hallmarks is a result of accommodation of tumor cells with their nearby milieu called tumor microenvironment (TME). Accommodation or adaptive responses is highly important for a cell to survive, without which no cell is allowed to take any further steps in tumorigenesis. Metabolism of cancer cells is largely depended on stroma. Composition and plasticity of cells within the stroma is highly affected from inflammatory setting of TME. Hypoxia which is a common event in many solid cancers, is known as one of the key hallmarks of chronic inflammation and the master regulator of metastasis. Transforming growth factor (TGF)-β is produced in the chronic inflammatory and chronic hypoxic settings, and it is considered as a cardinal factor for induction of all tumor hallmarks. Aging, obesity and smoking are the main predisposing factors of cancer, acting mainly through modulation of TME. [ABSTRACT FROM AUTHOR]

Background: Angiogenesis is a key and early step in tumorigenesis, and is known as a hallmark of solid tumors and a key promoter of tumor recurrence. Unlike normal tissue vessels, the architecture of the tumor vasculature is abnormal, being leaky, tortuous, fragile and blind-ended. Perivascular cells are either detached or absent, causing reduction of vascular integrity, an increase in vessel immaturity, incoherent perfusion, defective functionality and enhanced tumor dissemination and metastasis. The abnormal tumor vasculature along with the defective tumor vessel functionality finally causes bouts of hypoxia and acidity in the tumor microenvironment (TME), further reinvigorating tumor aggression. Interstitial hypertension or high interstitial fluid pressure (IFP) is an outcome of tumor hyper-permeability. High IFP can be a barrier for either effective delivery of anti-cancer drugs toward the TME or accumulation of drugs within the tumor area, thus promoting tumor resistance to therapy. Some tumors do, however, not undergo angiogenesis but instead undergo vessel co-option or vascular mimicry, thereby adding another layer of complexity to cancer development and therapy. Conclusions: Combination of anti-angiogenesis therapy with chemotherapy and particularly with immune checkpoint inhibitors (ICIs) is a promising strategy for a number of advanced cancers. Among the various approaches for targeting tumor angiogenesis, vascular normalization is considered as the most desired method, which allows effective penetration of chemotherapeutics into the tumor area, thus being an appropriate adjuvant to other cancer modalities. [ABSTRACT FROM AUTHOR]

Spinal cord injury (SCI) is a common devastating condition that causes neuronal loss and dysfunction. Neuroinflammation takes cardinal roles in the pathogenesis of SCI, and nucleotide‐binding domain‐like receptor protein 3 (NLRP3) inflammasome is a mediator of inflammatory reactions occurring in SCI patients. The present study was designed to survey possible relation between thoracic segments whereby injury occurs with the activity of NLRP3 inflammasome complex, and to find the influence of hormonal therapy on the outcomes. Adult male Wistar rats underwent contusion SCI model at three different thoracic segments T1, T6 and T12, then receiving subcutaneous injection of either 10 mg/kg melatonin or 25 μg/kg 17‐β estradiol (E2) every 12 hours until 72 hours post‐SCI. Inflammasome activity was assessed before and at the end of hormonal therapy. SCI rats showed decreased locomotor activity and myelination, and increased activity of the NLRP3, apoptosis‐associated speck‐like protein (ASC) and caspase‐1 at gene and protein levels. Release of interleukins (ILs) 18 and 1β was also augmented after SCI (P < 0.0.5). Hormonal therapy was most effective for targeting mRNA activity at T6 segment. Treatment with either melatonin or E2 caused a decrease in the protein activity of NLRP3 inflammasome at all segments (P < 0.0.5), except for T6 that NLRP3 protein had no response to melatonin. IL‐1β showed decreased activity in response to hormonal therapy at all segments, whilst IL‐18 protein had no change at T1 segment. It is understood that although no alteration in the activity of NLRP3 was found for SCI at different segments, the response to hormonal therapy was influenced by segment. Significance of the study: From our results, the NLRP3 inflammasome activity is not influenced by segment, but there are differences in the effect of hormonal therapy on inflammasome activity at different segments in response to melatonin or E2. These findings also provide the beneficial effects of melatonin or E2 on inflammation caused by spinal cord injury in different thoracic segments. Finally, these data can have therapeutic importance for hormone therapy of spinal cord injury. [ABSTRACT FROM AUTHOR]

Tumor cells need to cope with the host environment for survival and keep growing in hard conditions. This suggests that tumors must acquire characteristics more potent than what is seen for normal tissue cells, without which they are condemned to disruption. For example, cancer cells have more potent redox tolerance compared with normal cells, which is due to their high adaptation to an oxidative crisis. In addition, increased demand for bioenergetics and biosynthesis can cause a rise in nutrient uptake in tumors. Utilizing nutrients in low nutrient conditions suggests that tumors are also equipped with adaptive metabolic processes. Switching the metabolic demands toward glucose consumption upon exposure to the hypoxic tumor microenvironment, or changing toward using other sources when there is an overconsumption of glucose in the tumor area are examples of fitness metabolic systems in tumors. In fact, cancer cells in cooperation with their nearby stroma (in a process called metabolic coupling) can reprogram their metabolic systems in their favor. This suggests the high importance of stroma for meeting the metabolic demands of a growing tumor, an example in this context is the metabolic symbiosis between cancer‐associated fibroblasts with cancer cells. The point is that redox tolerance and metabolic reprogramming are interrelated, and that, without a doubt, disruption of redox tolerance systems by transient exposure to either oxidative or antioxidative loading, or targeting metabolic rewiring by modulation of tumor glucose availability, controlling tumor/stroma interactions, etc. can be effective from a therapeutic standpoint Highlights: Redox tolerance is more potent in cancer cells compared with normal cells."Transient" exposure to either oxidative or antioxidative loading is effective in disrupting redox tolerance in tumors.Tumoral cells withstand complex metabolic challenges (tensions) by exploiting various modalities including metabolic flexibility, plasticity, adaptation, fitness, addiction, competition, and symbiosis, enabling them to maintain metabolic and redox homeostasis and survive and proliferate (tumor growth).Mitochondria link metabolic reprogramming positively with redox tolerance and cancer metastasis.Metabolic interrelations between tumors with their nearby stroma suggest that nearly all cells within the TME possess the potential to reprogram metabolically.Improving the metabolic fitness of effector T cells along with their functionality and longevity are considered effective for enhancing the efficacy of immunotherapy. Glucose restoration to a therapeutic range is promising for this purpose. [ABSTRACT FROM AUTHOR]

Radiotherapy and chemotherapy are two famous modalities in tumor‐targeted therapy that lead to systemic and local toxicities for normal tissues. Moreover, several studies have confirmed that exposure of the tumor to radiation or chemotherapy drugs stimulate some signaling pathways in the tumor microenvironment (TME), leading to resistance of cancer cells to apoptosis, as well as promoting angiogenesis and tumor growth. Nuclear factor kappa B (NF‐κB) plays a central role in the regulation of inflammatory responses in both normal tissues and tumors via the release of several cytokines, regulation of prostaglandins, reduction/oxidation (redox) reactions, angiogenesis, and cell death. Upregulation of NF‐κB in normal tissues causes an appearance of inflammatory reactions and oxidative stress, whereas it regulates angiogenesis and suppresses apoptosis, leading to resistance to subsequent doses of radiation or chemotherapy. Selective inhibition of NF‐κB in experimental studies has shown promising results for tumor sensitization via apoptosis induction, inhibition of angiogenesis, and increasing delay of tumor growth. The use of some agents for NF‐κB inhibition has been shown to alleviate radiation/chemotherapy toxicities in normal cells/ tissues. In this current review, we explained the pivotal role of NF‐κB in both normal tissue toxicity and tumor resistance. We also discussed the promising strategies for overcoming these problems with regard to chemotherapy and radiotherapy. [ABSTRACT FROM AUTHOR]

Background: Prostate cancer is the second most common malignancy in men in the world, and radiotherapy is used as a standard treatment modality for this cancer. Although this treatment modality effectively kills prostate cancerous cells, it unavoidably irradiates the organs/tissues that are away from the treatment site. In this regard, radiation‐induced testicular toxicities following prostate radiotherapy can affect sexual function, reproduction, and quality of life in cancer survivors. This review summarizes the available data on testicular exposure to radiation during prostate radiotherapy and the consequences on testicular function. Methods: To illuminate the radiation‐induced testicular toxicities following prostate radiotherapy, a systematic search was conducted based on the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses guideline in PubMed, Web of Science, Scopus, Embase, and clinical trials electronic databases up to September 2018. According to a set of prespecified inclusion and exclusion criteria, 31 eligible articles providing data on testicular function following radiotherapy in patients with prostate cancer were included in the study. Results: According to the different radiotherapeutic techniques used for prostate cancer treatment, the total tumor dose and scattered testicular dose values were ranging from 36.25 to 78.00 Gy and 0.06 to 6.48 Gy, respectively. Luteinizing hormone and follicle‐stimulating hormone levels after prostate radiotherapy were significantly higher in comparison with the pretreatment levels. Around 60% of the studies showed that testosterone levels after prostate radiotherapy were significantly lower than the pretreatment levels. Furthermore, erectile dysfunction (ED), as an adverse side effect resulting from prostate radiotherapy, was reported and this complication is significantly correlated with lower satisfaction with sexual life. Testicular atrophy following prostate radiotherapy has also been observed and its frequency in patients with prior prostate radiotherapy is 2.5 times more than that in the patients without prior radiotherapy. Conclusion: The data revealed that the scattered dose to testicular tissues during prostate radiotherapy can lead to testicular atrophy, variation of the male sex hormones, and quality of sexual life. [ABSTRACT FROM AUTHOR]

Cancer incidences are growing and cause millions of deaths worldwide. Cancer therapy is one of the most important challenges in medicine. Improving therapeutic outcomes from cancer therapy is necessary for increasing patients' survival and quality of life. Adjuvant therapy using various types of antibodies or immunomodulatory agents has suggested modulating tumor response. Resistance to apoptosis is the main reason for radioresistance and chemoresistance of most of the cancers, and also one of the pivotal targets for improving cancer therapy is the modulation of apoptosis signaling pathways. Apoptosis can be induced by intrinsic or extrinsic pathways via stimulation of several targets, such as membrane receptors of tumor necrosis factor‐α and transforming growth factor‐β, and also mitochondria. Curcumin is a naturally derived agent that induces apoptosis in a variety of different tumor cell lines. Curcumin also activates redox reactions within cells inducing reactive oxygen species (ROS) production that leads to the upregulation of apoptosis receptors on the tumor cell membrane. Curcumin can also upregulate the expression and activity of p53 that inhibits tumor cell proliferation and increases apoptosis. Furthermore, curcumin has a potent inhibitory effect on the activity of NF‐κB and COX‐2, which are involved in the overexpression of antiapoptosis genes such as Bcl‐2. It can also attenuate the regulation of antiapoptosis PI3K signaling and increase the expression of MAPKs to induce endogenous production of ROS. In this paper, we aimed to review the molecular mechanisms of curcumin‐induced apoptosis in cancer cells. This action of curcumin could be applicable for use as an adjuvant in combination with other modalities of cancer therapy including radiotherapy and chemotherapy. [ABSTRACT FROM AUTHOR]

• TGF-β promotes anti-tumor immune cell exclusion and dysfunction. • TGF-β and PD-L1 show independent but complementary immunosuppressive potentials. • Anti-PD-L1/TGF-βRII trap agents enable PD-L1 saturation and TGF-β sequestration. • M7824 is more effective in PD-L1high or immune-excluded tumors. Immune checkpoint inhibitor (ICI) therapy suffers from tumor resistance and relapse in majority of patients due to the suppressive tumor immune microenvironment (TIME). Advances in the field have brought about development of fusion proteins able to target two signaling simultaneously and to exert maximal anti-cancer immunity. Bispecific inhibitors of transforming growth factor (TGF)-β signaling and programmed death-1 (PD-1) or programmed death-ligand 1 (PD-L1) are developed to reduce the rate of relapse and to achieve durable anti-cancer therapy. TGF-β is well-known for its immunosuppressive activity, and it takes critical roles in promotion of all tumor hallmarks. Bispecific anti-PD-(L)1/TGF-β inhibitors reinvigorate effector activity of CD8+ T and natural killer (NK) cells, hamper regulatory T cell (Treg) expansion, and increase the density of anti-tumor type 1 macrophages (M1). Responses to the bispecific approach are higher compared with solo anti-PD-(L)1 or TGF-β targeted therapy, and are seemingly more pronounced in human papillomavirus (HPV)+ patients. High expression of PD-L1 or immune-excluded phenotype in a tumor can also be markers of better response to the bispecific strategy. Besides, anti-PD-(L)1/TGF-β inhibitor therapy can be used safely with other therapeutic modalities including vaccination, radiation and chemotherapy. [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]

Radio- and chemotherapy are the most common cancer treatment modalities. They cause acute and late side effects on normal tissues, which is a burden for delivery of a high dose of radiation or drugs on tumor cells. In addition, tumor cells achieve adaptive responses to subsequent doses of radiation and chemotherapy, leading to tumor resistance and accelerated repopulation. Resistance to radiotherapy and chemotherapy can occur following adaptive responses, which itself is due to the release of large numbers of inter- and intracellular mediators by immune cells as well as other tumor microenvironment (TME) cells. Melatonin is a potent natural antioxidant and anti-inflammatory agent that protects against toxic side effects of radiation and chemotherapy. Furthermore, in some cancer cells, melatonin aids sensitizing cancer cells to therapy. Apoptosis is one of the main mechanisms of cell death following exposure to radiation and chemotherapy. Evidences have shown a direct relation between apoptosis induction in tumor cells with increased tumor delay regression and survival. Melatonin through modulation of several apoptosis mediators such as mitochondria, Bax, Bcl-2, endogenous ROS, and apoptosis receptors facilitate apoptosis. The current review aims to explain mechanisms of apoptosis induction following exposure to radiation and chemotherapy drugs. We also reviewed the modulatory effect of melatonin on apoptosis signaling pathways. Unlabelled Image [ABSTRACT FROM AUTHOR]

Cancer is the second cause of death worldwide. Chemotherapy and radiotherapy are the most common modalities for the treatment of cancer. Experimental studies have shown that inflammation plays a central role in tumor resistance and the incidence of several side effects following both chemotherapy and radiotherapy. Inflammation resulting from radiotherapy and chemotherapy is responsible for adverse events such as dermatitis, mucositis, pneumonitis, fibrosis, and bone marrow toxicity. Chronic inflammation may also lead to the development of second cancer during years after treatment. A number of anti‐inflammatory drugs such as nonsteroidal anti‐inflammatory agents have been proposed to alleviate chronic inflammatory reactions after radiotherapy or chemotherapy. Curcumin is a well‐documented herbal anti‐inflammatory agents. Studies have proposed that curcumin can help management of inflammation during and after radiotherapy and chemotherapy. Curcumin targets various inflammatory mediators such as cyclooxygenase‐2, inducible nitric oxide synthase, and nuclear factor κB (NF‐κB), thereby attenuating the release of proinflammatory and profibrotic cytokines, and suppressing chronic production of free radicals, which culminates in the amelioration of tissue toxicity. Through modulation of NF‐κB and its downstream signaling cascade, curcumin can also reduce angiogenesis, tumor growth, and metastasis. Low toxicity of curcumin is linked to its cytoprotective effects in normal tissues. This protective action along with the capacity of this phytochemical to sensitize tumor cells to radiotherapy and chemotherapy makes it a potential candidate for use as an adjuvant in cancer therapy. There is also evidence from clinical trials suggesting the potential utility of curcumin for acute inflammatory reactions during radiotherapy such as dermatitis and mucositis. [ABSTRACT FROM AUTHOR]

Despite great scientific breakthroughs toward understanding the identity of human hepatocellular carcinoma (HCC) mechanistically, there are still no clinically efficient therapeutic methods for this cancer. Melatonin (N‐acetyl‐5‐methoxytryptamine) is a multi‐tasking hormone that has long been known for its anti‐cancer activity against various human cancers including HCC, which is a focus of this review. PubMed database was searched for relevant articles with the keywords: hepatocellular carcinoma (HCC), melatonin, apoptosis, proliferation, invasion, angiogenesis, autophagy, oxidative stress, tumor immunity, and mitogen‐activated protein kinase (MAPK) focusing on just human cell lines and English language articles. Melatonin inhibits apoptosis resistance and activates both extrinsic and intrinsic pathways of apoptosis in HCC. Melatonin induces ensoplasmic reticulum (ER)‐ and autophagy‐mediated apoptosis in cancer cells. Melatonin works against cancer cell proliferation, motility, and invasiveness by modulating actions of a variety of transcription factors and related pathways. Melatonin also relieves an immunosuppressive state in HCC cancer cells through making a control over tumor‐derived exosomes. Both pro‐and anti‐oxidative functions of melatonin are necessary for combating HCC. Combination of melatonin with chemotherapy could also provide cumulative effects on cancer cells. Melatonin exerts most of these roles by acting on the members of MAPK family. [ABSTRACT FROM AUTHOR]

Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOXs) are key producer of reactive oxygen species in liver cells. Hepatic stellate cells (HSCs) and Kupffer cells (KCs) are the two key cells for expression of NOX in liver. KCs produce only NOX2, while HSCs produce NOX1, 2, and 4, all of which play essential roles in the process of fibrogenesis within liver. These NOX subtypes are contributed to induction of liver fibrosis by acting through multiple pathways including induction of HSC activation, proliferation, survival and migration, stimulation of hepatocyte apoptosis, enhancement of fibrogenic mediators, and mediation of an inflammatory cascade in both KCs and HSCs. Significance: KCs and HSCs are two key cells for production of NOX in liver in relation to the pathology of liver fibrosis. NOX subtypes 1, 2, and 4 are inducers of fibrogenesis in liver. NOX activation favors hepatocyte apoptosis, HSC activation, and KC‐mediated inflammatory cascade in liver, all of which are responsible for generation of liver fibrosis. [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]

• Aberrant B7x expression occurs in human cancers. • B7x preferentially expresses in APCs and tumor cells. • B7x promotes immune escape and associates with poor tumor cell differentiation. • B7x expression inversely correlates with PD-L1 expression profile. • B7x receptor is co-expressed with PD-1 on CD8+ T cells. • Anti-B7x can be used synergistically with anti-PD-(L)1 or anti-CTLA-4. • Bispecific inhibitors against B7x and other regulatory molecules are underway. B7x (also called B7-H4) is a co-inhibitory molecule of B7 family that is highly expressed in non-inflamed or cold cancers, and its aberrant expression is contributed to cancer progression and poor outcomes. B7x preferentially expresses on antigen-presenting cells (APCs) and in tumor cells, and it acts as an alternative anti-inflammatory immune checkpoint for hampering peripheral immune responses. Augmented infiltration of immunosuppressive cells, reduced proliferation and effector function of CD4+ and CD8+ T cells, and increased generation of regulatory T cells (Tregs) are outcomes of increased B7x activity in cancer. Evaluation of B7x in sera can be exploited as an effective biomarker of response in cancer patients. B7x overexpression generally occurs in programmed death-ligand 1 (PD-L1)- cancers and is involved in tumor resistance to anti-programmed death-1 (PD-1), anti-PD-L1 or anti-cytotoxic T lymphocyte associated antigen-4 (CTLA-4) therapy. Co-expression of B7x receptor with PD-1 on CD8+ T cells has made the anti-B7x a fruitful approach for reinvigoration of the functionality of exhausted T cells and is served as a complementary regimen in patients who are irresponsive to the common immune checkpoint inhibitor (ICI) therapy. An advance in the field is the development of bispecific antibodies against B7x with other regulatory molecules within tumor microenvironment (TME). [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) and spinal cord injury (SCI) are pathological events that lead to neuropathological conditions which have in consequence the initiation of pro‐inflammatory cytokine production. Neuroinflammation plays a key role in the secondary phase of both TBI and SCI after initial cell death. Activation of cytoplasmic inflammasome complexes is regarded as the essential step of neuroinflammation and a key trigger for neuronal death called pyroptosis. Inflammasome complexes are involved in activation of caspase‐1 which catalyzes the cleavage of pro‐interleukins into their active forms (including interleukin‐18 [IL‐18] and IL‐1β). The focus of this article is to discuss the time‐course and regulation of inflammasome assembly and activation during TBI and SCI and their targeting in designing therapeutic approaches. We particularly focus on the inflammasomes NLRP1 and NLRP3 which play a pivotal function during TBI and SCI in the central nervous system (CNS). [ABSTRACT FROM AUTHOR]

It is believed that oxidative stress is a key causing factor of liver damage induced by a variety of agents, and it is a major contributing factor in almost all conditions compromising liver function, including ischemia–reperfusion injury (IRI), nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), liver fibrosis, liver cirrhosis, and hepatocellular carcinoma (HCC). Liver is the organ that high concentration of melatonin (N‐acetyl‐5‐methoxytryptamine) accumulates, and it is the sole organ where circulating melatonin is metabolized. Melatonin is one of the best antioxidants that protects liver, and its metabolites also have antioxidative function. Melatonin exerts its antioxidative function directly through its radical scavenging ability and indirectly through stimulation of antioxidant enzymes. The antioxidative response from melatonin in liver affects from various factors, including its dosage, route, time and duration of administration, the type of oxidative‐induced agent and species aging. This indoleamine is also an effective and promising antioxidative choice for targeting liver IRI, NAFLD, NASH, fibrosis, cirrhosis, and HCC. [ABSTRACT FROM AUTHOR]

SDF-1a is a member of CXC chemokine family that plays a crucial role in stem cell migration, cell apoptosis and development. The role of intra-scrotal administration of SDF-1a in spermatogenesis of busulfan-treated rats was investigated in this study. Two injections of busulfan (15 mg/kg) with a 14 days interval between were given intraperitoneally to male Wistar rats. Rats were then treated for seven days with 500 ng/mL SDF-1a. Real-time PCR and immunohistochemistry were performed for evaluation of various cell markers for proliferation and spermatogenesis, and sperm parameters were assessed. In the SDF-1a group, there was a significant increase in testis weight, sperm count and viability. DAZL, DDX4, and TP2 showed increased expression levels in the SDF-1a group. PCNA and BrdU revealed highest expression rates in the SDF-1a group ( p ≤ 0.0001). These findings showed the protective role of SDF-1a in busulfan-induced testis injury most likely through stimulation of SSCs proliferation. [ABSTRACT FROM AUTHOR]

Preconditioning of mesenchymal stem cells (MSCs) with melatonin (MT) has shown promising results in animal models of myocardial infarction, renal ischemia and cerebral ischemia. Here, we use this strategy in the liver fibrosis induced by CCl4. There were five groups: normal, CCl4, CCl4 + vehicle, CCl4 + BMMSCs and CCl4 + MT-bone marrow (BM)-derived MSCs (MT-BMMSCs). CCl4 was injected twice weekly for 8 weeks and treatment either with cells or vehicle was performed at the beginning of week 5 with a single dose. BMMSCs were preconditioned with MT for 24 h before injection. MT-BMMSCs had a high ability of homing into the injured liver ( P ≤ 0.05 vs. BMMSCs). The CCl4 + MT-BMMSCs group showed higher percentage of glycogen storage but lower percentage of collagen and lipid accumulation ( P ≤ 0.05 vs. CCl4 + BMMSCs). The CCl4 + MT-BMMSCs group showed lower expressions of transforming growth factor-β1 (TGF-β1) and Bax and lower content of sera alanine aminotransferase (ALT) but higher expressions of matrix metalloproteinases (MMPs) and Bcl2 compared with the BMMSCs group ( P ≤ 0.05). The results showed the better therapeutic outcomes of MT preconditioning by probably improving cell homing and also better maintenance of the balance between matrix degrading and accumulating factors. [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]

Stroke is the consequence of limited blood flow to the brain with no established treatment to reduce the neurological deficits. Focusing on therapeutic protocols in targeting subventricular zone (SVZ) neurogenesis has been investigated recently. This study was designed to evaluate the effects of retinoic acid (RA)-pretreated Wharton's jelly mesenchymal stem cells (WJ-MSCs) in combination with triiodothyronine (T3) in the ischemia stroke model. Male Wistar rats were used to induce focal cerebral ischemia by middle cerebral artery occlusion (MCAO). There were seven groups of six animals: Sham, Ischemic, WJ-MSCs, RA-pretreated WJ-MSCs, T3, WJ-MSCs +T3, and RA-pretreated WJ-MSCs + T3. The treatment was performed at 24 h after ischemia, and animals were sacrificed one week later for assessments of retinoid X receptor β (RXRβ), brain-derived neurotrophic factor (BDNF), Sox2 and nestin in the SVZ. Pro-inflammatory cytokines in sera were measured at days four and seven after ischemia. RXRβ, BDNF, Sox2 and nestin had the significant expressions in gene and protein levels in the treatment groups, compared with the ischemic group, which were more vivid in the RA-pretreated WJ-MSCs + T3 ( p ≤ 0.05). The same trend was also resulted for the levels of TNF-α and IL-6 at four days after ischemia (p ≤ 0.05). In conclusion, application of RA-pretreated WJ-MSCs + T3 could be beneficial in exerting better neurotrophic function probably via modulation of pro-inflammatory cytokines. [ABSTRACT FROM AUTHOR]

There is a positive relation between decreases of triiodothyronine (T3) amounts and severity of stroke. The aim of this study was to evaluate the effect of exogenous T3 application on levels of neurogenesis markers in the subventricular zone. Cerebral ischemia was induced by middle cerebral artery occlusion in male Wistar rats. There were 4 experimental groups: sham, ischemic, vehicle, and treatment. Rats were injected with T3 (25 μg/kg, IV injection) at 24 hours after ischemia. Animals were sacrificed at day 7 after ischemia. There were high levels of brain-derived neurotrophic factor, nestin, and Sox2 expressions in gene and protein levels in the T3 treatment group ( P ≤ .05 vs ischemic group). Treatment group showed high levels of sera T3 and thyroxine (T4) but low levels of thyrotropin (TSH), tumor necrosis factor-α, and interleukin-6 ( P ≤ .05 vs ischemic group) at day 4 after ischemia induction. Findings of this study revealed the effectiveness of exogenous T3 application in the improvement of neurogenesis possibly via regulation of proinflammatory cytokines. [ABSTRACT FROM AUTHOR]

Resistance to immune checkpoint inhibitors (ICIs) is a common predicament in cancer immunotherapy, which requires urgent interventions. V-domain immunoglobulin suppressor of T cell activation (VISTA) or programmed death-1 homolog (PD-1H) is a molecule belong to the CD28/B7 family that acts as an immune checkpoint and a negative immune regulator. VISTA shows high expression within tumor microenvironment (TME) and shapes the immune landscape of this milieu into an immunosuppressive entity through blunting the activity of anti-tumor cells and strengthening the power of pro-tumor cells. The increased expression profile is occurring essentially after inhibition of other checkpoints, which indicates that VISTA can constitute a novel and complementary target in cancer immunotherapy. Combination of anti-VISTA with appropriate ICIs potentiates tumor immunogenicity through increasing the effector activity of T cells, and results in more pronounced responses. VISTA also serves as a prognostic biomarker in differentiating early- from late-stage cancer. In this review, we aimed to discuss about VISTA and its regulation within TME and focusing on its prognostic and therapeutic values in cancer immunotherapy. [Display omitted] • VISTA is overexpressed particularly on myeloid progeny. • VISTA is upregulated secondary to the anti-PD-1/PD-L1 or anti-CTLA-4. • VISTA activity on T cells is independent on PD-1/PD-L1 or CTLA-4. • VISTA is an independent prognostic marker. • Dual VISTA/PD-L1 blockade represents promising clinical efficacy. [ABSTRACT FROM AUTHOR]

Melatonin is known for being beneficial in targeting liver diseases. This study aimed to investigate whether melatonin post-treatment is capable of rat carbon tetrachloride (CCl4)-induced liver fibrosis reduction. Thirty-two male Sprague-Dawley rats were divided into 4 groups: normal; fibrosis with CCl4 injection (1 mL/kg) twice weekly for 8 weeks; phosphate-buffered saline (PBS); and melatonin (20 mg/kg) for a further 4 weeks on cessation of CCl4. At the beginning of week 13, liver tissue samples were used for hematoxylin-eosin (H&E), periodic acid-Schiff(PAS), Masson's trichrome (MT), and Oil Red O staining, quantitative real-time PCR (qRT-PCR) analysis of the matrix metalloproteinase-9 (MMP-9), MMP-13, transforming growth factor-β1 (TGF-β1), Bcl-2, and Bax genes as well as immunofluorescence (IF) of the first 3, and sera for measurement of aspartate aminotransferase (AST), alanine aminotransferase (ALT), albumin, and hydroxyproline. Chronic administration of CCl4 followed by considerable increase in tissue disruption, macro- and micro-vesicles, collagen, lipid droplets (LDs), AST, ALT, hydroxyproline, TGF-β1, and Bax, and decrease in glycogen depository, albumin, Bcl-2, MMP-9, and MMP-13; however, the pattern was reverse when it comes to melatonin treatment (for all p < 0.05). Our results reveal the beneficial aspects of melatonin in treatment of liver fibrosis probably via inhibition of TGF-β1expression. [ABSTRACT FROM AUTHOR]

Background: Nitric oxide (NO) as a signaling molecule plays a predominant role in different physiological and pathological processes in a variety of organs such as the gastrointestinal (GI) tract. It is produced from L-arginine by nitric oxide synthase (NOS), which in turn is inhibited by L-NG-nitroarginine methyl ester (L-NAME). Objectives: This study aimed to stereologically analyze colon under exposure of L-arginine and L-NAME in female Wistar rats. Materials and Methods: In this experimental study, 40 female rats (200 - 250 g, 8 weeks age) were divided into 5 groups (N = 8). Normal saline (2 mL/kg), L-arginine (200 mg/kg), L-NAME (20 mg/kg) and L-arginine + L-NAME (with the same doses) were administered i.p. for 3 days. After 2 weeks, the colon was removed, stained with hematoxylin and eosin (H and E) and evaluated under light microscopy. Colonic mucosal thickness, gland height and diameter, and total thickness of the wall were measured using optical software and analyzed by one-way ANOVA followed by Tukey's post hoc test using SPSS-16. P < 0.05 was considered statistically significant. Results: The data of the present work revealed relatively narrow ranges of decrease in mean variables compared to the control group, which was not significant. Conclusions: Despite the remarkable role of NOin GI tract, the results demonstrated no significant effect of L-arginine and L-NAME on colon parameters. [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]

Hypoxia is a known feature of solid tumors and a critical promoter of tumor hallmarks. Hypoxia influences tumor immunity in a way favoring immune evasion and resistance. Extreme hypoxia and aberrant hypoxia-inducible factor-1 (HIF-1) activity in tumor microenvironment (TME) is a drawback for effective immunotherapy. Infiltration and activity of CD8+ T cells is reduced in such condition, whereas regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) show high activities. Highly hypoxic TME also impairs maturation and activity of dendritic cell (DCs) and natural killer (NK) cells. In addition, the hypoxic TME positively is linked positively with metabolic changes in cells of immune system. These alterations are indicative of a need for hypoxia modulation as a complementary targeting strategy to go with immune checkpoint inhibitor (ICI) therapy. [Display omitted] • A rate of hypoxia is deemed as an adaptive response for immune effector function. • Extreme hypoxia and aberrant HIF-1 activity are immunosuppressive. • HIF-1α is a critical promoter of immunosuppressive TME. • Hypoxic TME impairs DC maturation, CD8+ T cell expansion and NK cell functionality. • Hypoxia-mediated preferential glycolysis and further lactate acidosis is immunosuppressive. [ABSTRACT FROM AUTHOR]

• Competition for IL-2 among immune cells will reduce the amount of IL-2 in TME. • High-dose IL-2 therapy is more effective in metastatic RCC than metastatic melanoma. • The activity of high-dose IL-2 therapy is attenuated by VEGF, IL-2Rα and MAGE-A3. • Toxicities related to the high-dose IL-2 may sometimes be life-threatening. • The current focus is over engineering pegylated IL-2 and IL-2 variants with selective activities. Interleukin (IL)-2 is a pleiotropic cytokine that displays opposing activities on immune system acting either in favor of or against cancer progression. Advanced/metastatic melanoma and renal cell carcinoma (RCC) are the two types of cancers that included most studies implemented for assessing the role of high-dose IL-2 therapy. The use of high-dose IL-2 therapy can, however, increase the rate of toxicities and interferes with the activity of endothelial cells (ECs) and effector T cells in tumor microenvironment (TME). This implies the need for adjusting strategies related to the cytokine therapy, such as suppressing signals that are interfering with the activity of this cytokine or the use of engineered IL-2 variants. The focus of this review is to discuss about pros and cons related to the IL-2 therapy and propose strategies to increase the efficacy of therapy. The outcomes of this literature will call for application of variants of IL-2 engineered to represent higher half-life and efficacy, and are more safe in the area of cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Myeloid-derived suppressor cells (MDSCs) are heterogeneous and poorly mature cells of innate immunity that their population is increased substantially in cancer patients. MDSCs represent three subsets including CD14+ monocytic (M), CD15+ granulocytic (G) and Lin− early precursor (e) cells. MDSCs release a number of factors that direct several tumorigenic-related events including immune evasion, angiogenesis and metastasis. Assessment of MDSCs can provide valuable information from cancer immunity state, and it can be an indicator of tumor prognosis. The cells can be targeted in combination with current immunotherapeutic schedules, and the outcomes were promising. The focus of this review is to provide an overview of MDSCs, their involvement in tumor-related immunosuppression, and their impact on cancer immunotherapy. Then, strategies are proposed to boost the power of immune system against MDSCs. [Display omitted] • M-MDSCs are CD14+, whereas G-MDSCs are CD15+. • Pre-treatment evaluation of MDSCs is of prognostic and therapeutic value. • MDSC recruitment into the tumor area is potentiated by chronic inflammation and hypoxia. • The dose of chemotherapy influences the fraction of circulatory MDSCs. • MDSC-targeting agents can be used for enhancing the efficacy of vaccination therapy. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC), and breast, ovarian, pancreatic and prostate cancers are generally considered as low immune-reactive cancers that represent either limited infiltration of immune cells or extensive infiltration of immunosuppressive T cells. Interaction between programmed death ligand 1 (PD-L1) with programmed death-1 receptor (PD-1) is important for immune evasion. Tumors positive for PD-L1 generally show higher responses to the immune checkpoint inhibition (ICI); however, the high presence of PD-L1 in a tumor is a predictor of poor prognosis. Triple negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, but responses to the ICI is meaningful. It seems that in a tumor both the PD-L1 expression and TIL infiltration is required for improving responses to the anti-PD-1/PD-L1 immunotherapy. Combination of anti-PD-1/PD-L1 with immune modulatory drugs, such as C-X-C chemokine receptor type 4 (CXCR4), poly (ADP-ribose) polymerase (PARP) or transforming growth factor (TGF)-β inhibitors has shown meaningful clinical benefits. • Anti-PD-1/PD-L1 drugs can be used safely in patients with cold cancers. • Previous therapy lines, PD-L1 expression status, TMB and the TIL fraction affect responses to the ICI. • Responses to ICI are generally higher in PD-L1+ cancers, the high PD-L1 presence, however, is a poor prognostic marker. • Anti-PD-1/PD-L1 acts in the late phase of T cell development, namely T cell expansion and maintenance. • Anti-CTLA-4 acts in the initial phase, namely priming phase. • Anti-PD-1/PD-L1 can be used appropriately in combination with anti-CTLA-4 • CXCR4, PARP or TGF-β inhibitors can be used as immune modulatory agents. [ABSTRACT FROM AUTHOR]

The conventional cancer treatment modalities such as radiotherapy and chemotherapy suffer from several limitations; hence, their efficiency needs to be improved with other complementary modalities. Hyperthermia, as an adjuvant therapeutic modality for cancer, can result in a synergistic effect on radiotherapy (radiosensitizer) and chemotherapy (chemosensitizer). Conventional hyperthermia methods affect both tumoral and healthy tissues and have low specificity. In addition, a temperature gradient generates in the tissues situated along the path of the heat source, which is a more serious for deep-seated tumors. Nanoparticles (NPs)-induced hyperthermia can resolve these drawbacks through localization around/within tumoral tissue and generating local hyperthermia. Although there are several review articles dealing with NPs-induced hyperthermia, lack of a paper discussing the combination of NPs-induced hyperthermia with the conventional chemotherapy or radiotherapy is tangible. Accordingly, the main focus of the current paper is to summarize the principles of NPs-induced hyperthermia and more importantly its synergic effects on the conventional chemotherapy or radiotherapy. The heat-producing nanostructures such as gold NPs, iron oxide NPs, and carbon NPs, as well as the non-heat-producing nanostructures, such as lipid-based, polymeric, and silica-based NPs, as the carrier for heat-producing NPs, are discussed and their pros and cons highlighted. Unlabelled Image [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]

Incapacitated immune system is a characteristic hallmark of solid tumors. Immune system within a tumor undergoes an imbalance in cellular dispersion and functionality. Effector cells are precluded from the invasive margin of tumor; instead, immune suppressor cells are present at high fractions. Conditions in the tumor microenvironment (TME) like altered metabolism, chronic hypoxia and chronic inflammation are the known predisposing factors, implicated in the immune malfunctioning. Deficiency of innate immune sensing mediated by checkpoint receptors including programmed death-1 receptor (PD-1), CTL-associated antigen-4 (CTLA-4) hijacked by tumor cells takes a major part of the blame, requiring a need for appropriate strategies in order to bring back the balance in the immune system. Immune checkpoint inhibitor (ICI) therapy has been in the eye of the current research rendering promising results. The story is not, however, that easy in which it is not so effective for Cold tumors, it may cause severe adverse effects, and that patients may acquire resistance to such therapy; this requires for updating the current knowledge about the immune ecosystem, using tumor type dependent dose calculation and exploiting proper adjuvants in order for evolving desired responses. Unlabelled Image [ABSTRACT FROM AUTHOR]

Chemotherapy is an effective therapeutic modality which is commonly used for battling various cancers. However, several side effects induced by chemotherapeutic drugs would limit their clinical use. The present systematic review aims to evaluate the role of curcumin/curcuminoids co-administration during gastric cancer chemotherapy. This systematic review was done according to PRISMA guidelines and a full systematic search in the electronic databases up to May 2020 using search terms in the titles and abstracts for the identification of relevant literature. 279 articles were found in electronic databases and 175 articles screened by title and abstract. Finally, 13 articles were included in this systematic review according to our inclusion and exclusion criteria. The findings indicated that gastric cancer chemotherapy induces cytotoxicity effects in various ways including a decrease of cell viability, colony formation, metastasis, tumor growth, and weight, as well as elevation of apoptosis pathway, oxidative stress pathway compared to the control group. Co-administration of curcumin/curcuminoids with chemotherapy synergistically increased the effects of anti-cancer chemotherapy compared to the group solo treated with chemotherapeutic agents. Also, in chemoresistance gastric cancer cells, co-administration of curcumin reduced chemoresistance mainly through the reduction of NF-κB activation and elevation of apoptosis. According to the findings, the use of curcumin/curcuminoids during gastric cancer chemotherapy has chemosensitizing effects, and also it can reduce chemoresistance in gastric cancer. Unlabelled Image [ABSTRACT FROM AUTHOR]

Tumors are dynamic tissue masses, so requiring continuous exposure to the host cells, nurturing them into pave a path for tumor growth and metastasis. C-X-C chemokine ligand 12 (CXCL12)/C-X-C chemokine receptor type 4 (CXCR4) is the key signaling for such aim. Gathering knowledge about the activity within this axis would deepen our insight into the utmost importance this signaling taken to attract and cross-connect multiple cells within the tumor microenvironment (TME) aiming for tumor progression and metastasis. The concept behind this review is to underscore the multi-tasking roles taken by CXCL12/CXCR4 signaling in tumor metastasis, and to also suggest some strategies to target the activities within this axis. Unlabelled Image [ABSTRACT FROM AUTHOR]

There is a dynamic heterogeneous cellularity dispersing within the edge and core of tumor. This heterogeneity is predominantly for developing adaptive mechanisms as a response to various harm situations. Edge cells are more quiescent, invasive and resistant than cells seeded in the core. Higher proliferation and thus more cellular density is a significant characteristic of core cells. An increase in the number of resistant cells in higher stage cancers is a predictable phenomenon, which is partly due to core-to-edge cellular transitioning, and thus expanding the edge area of tumor. The question here is that what differences are in the tumor infrastructure causing these variations and how it can be related to therapy? Here, we have a special focus over hypoxia as a dominant contributing factor for this cellular dispersing, challenging views toward this context and push them to our direction. It would be fair to announce that combine targeting for both hypoxia inducible factor (HIF)-1α and HIF-2α may hold a therapeutic promise for high-stage tumors, but an ongoing research is required to direct this hypothesis toward certainty. Unlabelled Image [ABSTRACT FROM AUTHOR]

Cancer associated fibroblasts (CAFs) as the dominant, long-lived and highly plastic cells within the tumor microenvironment (TME) with multi-faceted roles that are endowed with tumor aggressive features. They can instruct and shape the stroma of tumor into being a highly qualified bed for cellular recruitment, differentiation and plasticity in the host tissue or secondary organ/s. In this Review, we have a discussion over CAF reprogramming as a general concept, inducers and outcomes, pursued by suggesting potential strategies to combat this key promoter of tumor. Image 1 [ABSTRACT FROM AUTHOR]

Cancer is a disease of high complexity. Resistance to therapy is a major challenge in cancer targeted therapies. Overcoming this resistance requires a deep knowledge of the cellular interactions within tumor. Natural killer (NK) cells and cytotoxic T lymphocytes (CTLs) are the main anti-cancer immune cells, while T regulatory cells (Tregs) and cancer associated fibroblasts (CAFs) facilitate immune escape of cancer cells. Melatonin is a natural agent with anti-cancer functions that has also been suggested as an adjuvant in combination with cancer therapy modalities such as chemotherapy, radiotherapy, immunotherapy and tumor vaccination. One of the main effects of melatonin is regulation of immune responses against cancer cells. Melatonin has been shown to potentiate the activities of anti-cancer immune cells, as well as attenuating the activities of Tregs and CAFs. It also has a potent effect on the mitochondria, which may change immune responses against cancer. In this review, we explain the mechanisms of immune regulation by melatonin involved in its anti-cancer effects. Mechanisms of apoptotic resistance of cancer cells and sensitizing effect of melatonin. NF-κB plays a central role in the resistance of cancer cells to apoptosis. Melatonin via preventing nuclear translocation of NF-κB augments apoptosis rate. Inhibition of PI3K/mTOR pathway by melatonin is also involved in the progression of apoptosis in cancer cells. Image 1 [ABSTRACT FROM AUTHOR]

Radiotherapy is one of the most common treatment modalities for controlling a wide range of tumors. However, it has been shown that radiotherapy alone is unable to completely eradicate some tumors and could be associated with a high possibility of tumor recurrence. To date, various experimental and clinical studies have been conducted to explore some efficient targets within tumor microenvironment (TME) to enhance tumor response to radiotherapy; thus help eliminate or eradicate tumors. Although targeting DNA damage responses (DDRs) is associated with severe toxicities, studies in recent decade suggest that inhibition of some apoptosis/survival targets within TME is promising. This is also associated with changes in the numbers of T regulatory cells (Tregs) and cytotoxic T lymphocytes (CTLs). The inhibition of cyclooxygenase-2 (COX-2), phosphoinositide 3-kinase (PI3K), mammalian target of rapamycin (mTOR), mitogen-activated protein kinases (MAPKs) and vascular endothelial growth factor (VEGF) have also shown promising results. The combination of receptor tyrosine kinase (RTK) inhibitors with radiotherapy is interesting as well as the clinical use of some drugs and antibodies. Epidermal growth factor receptor (EGFR) inhibitors are the most common RTK inhibitors. Some clinical trials in recent years have shown very interesting results for immune checkpoint inhibitors (ICIs), especially programmed death-ligand 1 (PD-L1) and CTLs–associated antigen 4 (CTLA-4) inhibitors. It has been suggested that administration of ICIs during or after hypofractionated radiotherapy could lead to best results. In this review, we explain TME response to radiotherapy and potential targets for sensitization of cancer cells to radiotherapy. • A high dose of ionizing radiation is more efficient to release immune antigen stimulators. • The balance between immunogenic vs tolerogenic cell death plays a key role in the fate of radiotherapy. • Targeting apoptosis resistant mediators is the most common aim for sensitization of cancer cells to radiotherapy. • MAPKs, NFkB, COX-2, PI3K, mTOR, EGFR, HIF-1, PDL-1 and CTLA-4 are the most interesting targets for induction of apoptosis. • Immune system responses to radiotherapy can be change by radiation dose and time. [ABSTRACT FROM AUTHOR]