The role of interleukin-2 in graft-versus-host disease pathogenesis, prevention and therapy.

Graft-versus-host disease (GVHD) is a significant complication following allogeneic hematopoietic cell transplantation (allo-HCT), posing substantial risks to patient survival. In the late follow-up phase of transplanted patients, GVHD is also a major cause of morbidity and disability, mostly due to low response to first-line steroids and the lack of effective standard therapies in the second line. This review provides a description of GVHD pathogenesis, with a focus on the central role of Interleukin-2 (IL-2). IL-2 is one of the critical mediators in the complex pathogenesis of GVHD, contributing to the intricate balance between regulatory T cells (Tregs) and effector T cells (Teffs). Due to this pivotal role, several studies investigate the potential of IL-2 as a therapeutic option for GVHD management. We discuss the outcomes of low-dose IL-2 therapies and their impact on Treg proliferation and steroid dependency reduction. Additionally, the effects of combining IL-2 with other treatments, such as extracorporeal photopheresis (ECP) and Treg-enriched lymphocyte infusions, are highlighted. Novel approaches, including modified IL-2 complexes and IL-2 receptor blockade, are explored for their potential in selectively enhancing Treg function and limiting Teff activation. The evolving understanding of IL-2's pivotal role in immune regulation presents promising prospects for applying treatment and prevention strategies for GVHD.

Ferroptosis as a promising targeted therapy for triple negative breast cancer.

PURPOSE: Triple negative breast cancer (TNBC) is a challenging subtype characterized by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression. Standard treatment options are limited, and approximately 45% of patients develop distant metastasis. Ferroptosis, a regulated form of cell death triggered by iron-dependent lipid peroxidation and oxidative stress, has emerged as a potential targeted therapy for TNBC. METHODS: This study utilizes a multifaceted approach to investigate the induction of ferroptosis as a therapeutic strategy for TNBC. It explores metabolic alterations, redox imbalance, and oncogenic signaling pathways to understand their roles in inducing ferroptosis, characterized by lipid peroxidation, reactive oxygen species (ROS) generation, and altered cellular morphology. Critical pathways such as Xc-/GSH/GPX4, ACSL4/LPCAT3, and nuclear factor erythroid 2-related factor 2 (NRF2) are examined for their regulatory roles in ferroptosis and their potential dysregulation contributing to cancer cell survival and resistance. RESULTS: Inducing ferroptosis has been shown to inhibit tumor growth, enhance the efficacy of conventional therapies, and overcome drug resistance in TNBC. Lipophilic antioxidants, GPX4 inhibitors, and inhibitors of the Xc- system have been demonstrated to be potential ferroptosis inducers. Additionally, targeting the NRF2 pathway and exploring other ferroptosis regulators, such as ferroptosis suppressor protein 1 (FSP1), and the PERK-eIF2α-ATF4-CHOP pathway, may offer novel therapeutic avenues. CONCLUSION: Further research is needed to understand the mechanisms, optimize therapeutic strategies, and evaluate the safety and efficacy of ferroptosis-targeted therapies in TNBC treatment. Overall, targeting ferroptosis represents a promising approach to improving treatment outcomes and overcoming the challenges posed by TNBC.

The role of AMPK in pancreatic cancer: from carcinogenesis to treatment.

Pancreatic cancer has doubled over the previous two decades. Routine therapies are becoming incredibly resistant and failing to compensate for the burden caused by this aggressive neoplasm. As genetic susceptibility has always been a highlighted concern for this disease, identifying the molecular pathways involved in the survival and function of pancreatic cancer cells provides insight into its variant etiologies, one of which is the role of AMPK. This regulating factor of cell metabolism is crucial in the homeostasis and growth of the cell. Herein, we review the possible role of AMPK in pancreatic cancer while considering its leading effects on glycolysis and autophagy. Then, we assess the probable therapeutic agents that have resulted from the suggested pathways. Studying the underlying genetic changes in pancreatic cancer provides a chance to detect and treat patients suffering from advanced stages of the disease, and those who have given up their hope on conventional therapies can gain an opportunity to combat this cancer.

Circulating miRNA and circulating tumor DNA application as liquid biopsy markers in gastric cancer.

Liquid biopsy has been investigated as a novel method to overcome the numerous challenges in gastric cancer (GC) management. This non-invasive, feasible, and easy-to-repeat method has been shown to be cost-effective and capable of increasing diagnostic sensitivity and prognostic assessment. Additionally, it is potentially accurate to aid decision-making and personalized treatment planning. MicroRNA (miRNA) and circulating tumor DNA (ctDNA) markers can enhance GC management in various aspects, including diagnosis (mainly earlier diagnosis and the ability to perform population-based screening), prognosis (more precise stratification of prognosis), and treatment (including more accurate prediction of treatment response and earlier detection of resistance to the treatment). Concerning the treatment-related application, miRNAs' mimics and antagonists (by using two main strategies of restoring tumor suppressor miRNAs and inhibiting oncogene miRNAs) have been shown to be effective therapeutic agents. However, these need to be further validated in clinical trials. Furthermore, novel delivery systems, such as lipid-based vectors, polymeric-based vectors, and exosome-based delivery, have been developed to enhance the performance of these agents. Moreover, this paper explores the current detection and measuring methods for these markers. These approaches are categorized into direct methods (e.g., Chem-NAT, HTG EdgeSeq, and Multiplex Circulating Fireplex) and indirect methods (e.g., Reverse transcription-quantitative polymerase chain reaction (RT-qPCR), qPCR, microarray, and NGS) for miRNA detection. For ctDNA measurement, main core technologies like NGS, digital PCR, real-time PCR, and mass spectrometry are suggested.

NLRP3 inflammatory pathway. Can we unlock depression?

Depression holds the title of the largest contributor to worldwide disability, with the numbers expected to continue growing. Currently, there are neither reliable biomarkers for the diagnosis of the disease nor are the current medications sufficient for a lasting response in nearly half of patients. In this comprehensive review, we analyze the previously established pathophysiological models of the disease and how the interplay between NLRP3 inflammasome activation and depression might offer a unifying perspective. Adopting this inflammatory theory, we explain how NLRP3 inflammasome activation emerges as a pivotal contributor to depressive inflammation, substantiated by compelling evidence from both human studies and animal models. This inflammation is found in the central nervous system (CNS) neurons, astrocytes, and microglial cells. Remarkably, dysregulation of the NLRP3 inflammasome extends beyond the CNS boundaries and permeates into the enteric and peripheral immune systems, thereby altering the microbiota-gut-brain axis. The integrity of the brain blood barrier (BBB) and intestinal epithelial barrier (IEB) is also compromised by this inflammation. By emphasizing the central role of NLRP3 inflammasome activation in depression and its far-reaching implications, we go over each area with potential modulating mechanisms within the inflammasome pathway in hopes of finding new targets for more effective management of this debilitating condition.

Targeting ferroptosis as a cell death pathway in Melanoma: From molecular mechanisms to skin cancer treatment.

Melanoma, the most aggressive form of human skin cancer, has been under investigation to reach the most efficient treatment. Surgical resection for early-diagnosed primary melanoma, targeted therapies, and immune checkpoint inhibitors for advanced/metastatic melanoma is the best clinical approach. Ferroptosis, a newly identified iron-dependent cell death pathway, which is morphologically and biochemically different from apoptosis and necrosis, has been reported to be involved in several cancers. Ferroptosis inducers could provide therapeutic options in case of resistance to conventional therapies for advanced/metastatic melanoma. Recently developed ferroptosis inducers, MEK and BRAF inhibitors, miRNAs such as miR-137 and miR-9, and novel strategies for targeting major histocompatibility complex (MHC) class II in melanoma can provide new opportunities for melanoma treatment. Combining ferroptosis inducers with targeted therapies or immune checkpoint inhibitors increases patient response rates. Here we review the mechanisms of ferroptosis and its environmental triggers. We also discuss the pathogenesis and current treatments of melanoma. Moreover, we aim to elucidate the relationship between ferroptosis and melanoma and ferroptosis implications to develop new therapeutic strategies against melanoma.

The Role of Ketogenic Diet in the Treatment of Neuroblastoma.

The ketogenic diet (KD) was initially used in 1920 for drug-resistant epileptic patients. From this point onward, ketogenic diets became a pivotal part of nutritional therapy research. To date, KD has shown therapeutic potential in many pathologies such as Alzheimer's disease, Parkinson's disease, autism, brain cancers, and multiple sclerosis. Although KD is now an adjuvant therapy for certain diseases, its effectiveness as an antitumor nutritional therapy is still an ongoing debate, especially in Neuroblastoma. Neuroblastoma is the most common extra-cranial solid tumor in children and is metastatic at initial presentation in more than half of the cases. Although Neuroblastoma can be managed by surgery, chemotherapy, immunotherapy, and radiotherapy, its 5-year survival rate in children remains below 40%. Earlier studies have proposed the ketogenic diet as a possible adjuvant therapy for patients undergoing treatment for Neuroblastoma. In this study, we seek to review the possible roles of KD in the treatment of Neuroblastoma.

The signaling and the metabolic differences of various CAR T cell designs.

Chimeric antigen receptor (CAR) T cell therapy is introduced as an effective, rapidly evolving therapeutic to treat cancer, especially cancers derived from hematological cells, such as B cells. CAR T cell gene constructs combine a tumor-targeting device coupled to the T cell receptor (TCR) zeta chain domain with different signaling domains such as domains derived from CD28 or 4-1BB (CD137). The incorporation of each specific co-stimulatory domain targets the immunometabolic pathways of CAR T cells as well as other signaling pathways. Defining the immunometabolic and signaling pathways by which CAR T cells become and remain active, survive, and eliminate their targets may represent a huge step forward in this relatively young research field as the CAR gene can be tailored to gain optimal function also for solid tumors with elaborate immunosuppression and protective stroma. There is a close relationship between different signaling domains applied in CAR T cells, and difficult to evaluate the benefit from different tested CAR gene constructs. In this review, we attempt to collect the latest findings regarding the CAR T cell signaling pathways that affect immunometabolic pathways.

Nanoimmunoengineering strategies in cancer diagnosis and therapy.

Cancer immunotherapy strategies in combination with engineered nanosystems have yielded beneficial results in the treatment of cancer and their application is increasing day by day. The pivotal role of stimuli-responsive nanosystems and nanomedicine-based cancer immunotherapy, as a subsidiary discipline in the field of immunology, cannot be ignored. Today, rapid advances in nanomedicine are used as a platform for exploring new therapeutic applications and modern smart healthcare management strategies. The progress of nanomedicine in cancer treatment has confirmed the findings of immunotherapy in the medical research phase. This study concentrates on approaches connected to the efficacy of nanoimmunoengineering strategies for cancer immunotherapies and their applications. By assessing improved approaches, different aspects of the nanoimmunoengineering strategies for cancer therapies are discussed in this study.

Diet Influences Immunotherapy Outcomes in Cancer Patients: A Literature Review.

The outbreak of immunotherapy has revolutionized cancer treatment. Despite the results confirming the effectiveness of immunotherapy, some studies have reported poor responsiveness to this therapeutic approach. The effectiveness of immunotherapy is dependent on numerous factors related to patients' lifestyles and health status. Diet, as an essential component of lifestyle, plays a major role in determining immunotherapy outcomes. It can significantly influence the body, gut microbiome composition, and metabolism, both in general and in tumor microenvironment. Consuming certain diets has resulted in either improved or worsened outcomes in patients receiving immunotherapy. For example, several recent studies have associated ketogenic, plant-based, and microbiome-favoring diets with promising outcomes. Moreover, obesity and dietary deprivation have impacted immunotherapy responsiveness, yet the studies are inconsistent in this context. This narrative review aims to integrate the results from many articles that have studied the contribution of diet to immunotherapy. We will start by introducing the multiple effects of dietary status on cancer progression and treatment. Then we will proceed to discuss various regimens known to affect immunotherapy outcomes, including ketogenic, high-fiber, and obesity-inducing diets and regimens that either contain or lack specific nutrients. Finally, we will elaborate on how composition of the gut microbiome may influence immunotherapy.

The pro-tumorigenic responses in metastatic niches: an immunological perspective.

Metastasis is the leading cause of mortality related to cancer. In the course of metastasis, cancer cells detach from the primary tumor, enter the circulation, extravasate at secondary sites, and colonize there. All of these steps are rate limiting and decrease the efficiency of metastasis. Prior to their arrival, tumor cells can modify the secondary sites. These favorable microenvironments increase the probability of successful dissemination and are referred to as pre-metastatic niches. Cancer cells use different mechanisms to induce and maintain these niches, among which immune cells play prominent roles. The immune system, including innate and adaptive, enhances recruitment, extravasation, and colonization of tumor cells at distant sites. In addition to immune cells, stromal cells can also contribute to forming pre-metastatic niches. This review summarizes the pro-metastatic responses conducted by immune cells and the assistance of stromal cells and endothelial cells in the induction of pre-metastatic niches.

The role of dendritic cells in neuroblastoma: Implications for immunotherapy.

Neuroblastoma is a solid tumor, which is originated from some neural tissues. The immune system including the innate and adaptive immune system fights against this tumor. Dendritic cells (DCs) play an important role in this way by recognizing tumor antigens and activating specific types of T cells. These cells are derived from monocytes that are induced by inflammatory factors secreted by different cells in the tumor microenvironment (TME). There are different types of DCs, including monocyte-derived DCs (moDC), plasmacytoid DCs (pDC), conventional DCs type 1 and 2 (cDC1 and cDC2), and Langerhans cells. DCs connect the innate and the adaptive part of the immune system and have an important role in anti-tumor immunity. There are some vaccines that involve specific types of DCs, which can be used to prevent neuroblastoma. Also, we can use the combination of inflammatory factors and DCs as a substitute for chemotherapy.

AMPK's double-faced role in advanced stages of prostate cancer.

Prostate cancer (PCa) is the second leading cause of cancer deaths in men. Unfortunately, a very limited number of drugs are available for the relapsed and advanced stages of PCa, adding only a few months to survival; therefore, it is vital to develop new drugs. 5´ AMP-activated protein kinase (AMPK) is a master regulator of cell metabolism. It plays a significant role in the metabolism of PCa; hence, it can serve well as a treatment option for the advanced stages of PCa. However, whether this pathway contributes to cancer cell survival or death remains unknown. The present study reviews the possible pathways by which AMPK plays role in the advanced stages of PCa, drug resistance, and metastasis: (1) AMPK has a contradictory role in promoting glycolysis and the Warburg effect which are correlated with cancer stem cells (CSCs) survival and advanced PCa. It exerts its effect by interacting with hypoxia-induced factor 1 (HIF1) α, pyruvate kinase 2 (PKM2), glucose transporter (GLUT) 1 and pyruvate dehydrogenase complex (PDHC), which are key regulators of glycolysis; however, whether it promotes or discourage glycolysis is not conclusive. It can also exert an anti-CSC effect by negative regulation of NANOG and epithelial-mesenchymal transition (EMT) transcription factors, which are the major drivers of CSC maintenance; (2) the regulatory effect of AMPK on autophagy is also noticeable. Androgen receptors' expression increases AMPK activation through Calcium/calmodulin-dependent protein kinase 2 (CaMKK2) and induces autophagy. In addition, AMPK itself increases autophagy by downregulating the mammalian target of rapamycin complex (mTORC). However, whether increased autophagy inhibits or promotes cell death and drug resistance is contradictory. This study reveals that there are numerous pathways other than cell metabolism by which AMPK exerts its effects in the advanced stages of PCa, making it a priceless treatment target. Finally, we mention some drugs developed to treat the advanced stages of PCa by acting on AMPK.

Investigation of BRCAness associated miRNA-gene axes in breast cancer: cell-free miR-182-5p as a potential expression signature of BRCAness.

The concept of the 'BRCAness' phenotype implies the properties that some sporadic breast cancers (BC) share with BRCA1/2-mutation carriers with hereditary BC. Breast tumors with BRCAness have deficiencies in homologous recombination repair (HRR), like BRCA1/2-mutation carriers, and consequently could benefit from poly-(ADP)-ribose polymerase (PARP) inhibitors and DNA-damaging chemotherapy. Triple-negative breast cancers (TNBC) show a higher frequency of BRCAness than the other BC subtypes. Therefore, looking for BRCAness-related biomarkers could improve personalized management of TNBC patients. microRNAs (miRNAs) play a pivotal role in onco-transcriptomic profiles of tumor cells besides their suitable features as molecular biomarkers. The current study aims to evaluate the expression level of some critical miRNAs-mRNA axes in HRR pathway in tumors and plasma samples from BC patients. The expression levels of three multi-target miRNAs, including miR-182-5p, miR-146a-5p, and miR-498, as well as six downstream HRR-related protein-coding genes, have been investigated in the breast tumors and paired adjacent normal tissues by Real-time PCR. In the next step, based on the results derived from the previous step, we examined the level of cell-free miR-182-5p in the blood plasma samples from the patients. Our results highlight the difference between TNBC and non-TNBC tumor subgroups regarding the dysregulation of the key miRNA/mRNA axes involved in the HRR pathway. Also, for the first time, we show that the level of cell-free miR-182-5p in plasma samples from BC patients could be a clue for screening BC patients eligible for receiving PARP inhibitors through a personalized manner. Altogether, some sporadic BC patients, especially sporadic TNBC, have epigenetically dysregulated HRR pathway that could be identified and benefit from BRCAness-specific therapeutic agents.

Tumor-infiltrating lymphocyte therapy for lung cancer and its future paradigms.

INTRODUCTION: Lung cancer is the leading cause of cancer death, with an estimated 1.8 million deaths contributing to this cancer in 2020. Despite advances in treatment options and various approaches being attempted, the survival rate remains low. AREAS COVERED: In this review, we aim to provide an overview of the efficacy of tumor-infiltrating lymphocyte (TIL) therapy for lung cancer based on existing clinical trials. We also discuss the current challenges and future landscape of this treatment modality. EXPERT OPINION: Lung cancer can be a suitable candidate for TIL therapy due to its high mutational burden. Specifically, it has shown promising results for non-small cell lung cancer resistant to immune checkpoint inhibitors. Still, there are many restrictions associated with the ex vivo expansion and delivery of TILs, limiting their availability. For this reason, applying TIL for the treatment of lung cancer has not been extensively investigated yet and only a few clinical trials have shown favorable results of TIL therapy in patients with lung cancer. Thus, facilitating this costly, labor-intensive and time-consuming process is of utmost importance to increase the number of performed studies and to detect eligible patients who could benefit most from this treatment modality.

Interleukin 17, the double-edged sword in atherosclerosis.

Cardiovascular diseases, including atherosclerosis, are the number one cause of death worldwide. These diseases have taken the place of pneumonia and other infectious diseases in the epidemiological charts. Thus, their importance should not be underestimated. Atherosclerosis is an inflammatory disease. Therefore, immunological signaling molecules and immune cells carry out a central role in its etiology. One of these signaling molecules is interleukin (IL)-17. This relatively newly discovered signaling molecule might have a dual role as acting both pro-atherogenic and anti-atherogenic depending on the situation. The majority of articles have discussed IL-17 and its action in atherosclerosis, and it may be a new target for the treatment of patients with this disease. In this review, the immunological basis of atherosclerosis with an emphasis on the role of IL-17 and a brief explanation of the role of IL-17 on atherosclerogenic disorders will be discussed.

Exploring the application of immunotherapy against HIV infection in the setting of malignancy: A detailed review article.

According to the Joint United Nations Programme on HIV/AIDS (UNAIDS), as of 2019, approximately 42.2 million people have died from acquired immunodeficiency syndrome (AIDS)-related illnesses since the start of the epidemic. Antiretroviral therapy (ART) has significantly reduced mortality, morbidity, and incidence of the human immunodeficiency virus (HIV)/AIDS-defining cancers, taming once-dreaded disease into a benign chronic infection. Although the treatment has prolonged the patients' survival, general HIV prevalence has increased and this increase has dovetailed with an increasing incidence of Non-AIDS-defining cancers (NADCs) among people living with HIV (PLWH). This is happening when new promising approaches in both oncology and HIV infection are being developed. This review focuses on recent progress witnessed in immunotherapy approaches against HIV-related, Non-AIDS-defining cancers (NADCs), and HIV infection.

The role of myeloid-derived suppressor cells in lung cancer and targeted immunotherapies.

INTRODUCTION: Lung cancer is the deadliest cancer in both sexes combined globally due to significant delays in diagnosis and poor survival. Despite advances in the treatment of lung cancer, the overall outcomes remain poor and traditional chemotherapy fails to provide long-term benefits for many patients. Therefore, new treatment strategies are needed to increase overall survival. Myeloid-derived suppressor cells (MDSCs) are immunosuppressive cells taking part in lung cancer, as has been described in other types of tumors. MDSCs immunosuppressive activity is mediated by arginases (ARG-1 and ARG-2), nitric oxide (NO), reactive oxygen species (ROS), peroxynitrite, PD-1/PD-L1 axis, and different cytokines. MDSCs can be a target for lung cancer immunotherapy by inducing their differentiation into mature myeloid cells, elimination, attenuation of their function, and inhibition of their accumulation. AREAS COVERED: In this review, the immunosuppressive function of MDSCs, their role in lung cancer, and strategies to target them, which could result in increased efficacy of immunotherapy in patients with lung cancer, are discussed. EXPERT OPINION: Identification of important mechanisms and upstream pathways involved in MDSCs functions paves the way for further preclinical and clinical lung cancer research, which could lead to the development of novel therapeutic approaches.

TGF-ß signaling and the interaction between platelets and T-cells in tumor microenvironment: Foes or friends?

T-cells, as the main immune cells in fighting against cancer cells, are usually overwhelmed by many factors. Tumor microenvironment (TME) changes are one of the factors that can limit T-cells functions. On the other hand, platelets which are known as the main source of transforming growth factor-ß (TGF-ß) in TME, are seemingly insignificant immune cells that can affect T-cell functions. There is a hypothesis that platelets might prevent tumor growth by stimulating cellular immunity, especially T-cells in pre-cancer status while they can inhibit T-cells and stimulate tumor growth in the advanced stage of cancer. Therefore, platelets could act as a double-edged sword in the activation of T-cells under pre-cancer and advanced stages of cancer conditions. In this review, the interaction between platelets and T cells in pre-cancer and advanced stages of cancer and the role of TGF-ß signaling in different stages of cancer will be discussed.