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Autoimmune diseases, especially among young people in the US, are one of the leading causes of morbidity and death. The immune responses are the fundamental pathogenicity of autoimmune disorders. The equilibrium between stimulatory and inhibitory signals is critical for the stimulation, migration, survival, and T cell-related immune responses. The B7 family can substantially regulate T cell-mediated immune responses. Nevertheless, recent breakthroughs in immune checkpoint blockade in cancer immunotherapy have facilitated autoimmune diseases, especially among the prone populations. In the current study, we tried to concisely review the role of the B7 family in regulating immune reactions and the influence of immune checkpoint inhibitors on autoimmunity development., (© 2022 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Tumor-associated macrophages (TAMs) are among the abundant cell populations of the tumor microenvironment (TME), which have pivotal roles in tumor development, chemoresistance, immune evasion, and metastasis. Growing evidence indicates that TAMs and the cross-talk between TAMs and tumoral endothelial cells can substantially contribute to tumor angiogenesis, which is considered a vital process for cancer development. Besides, tumoral endothelial cells can regulate the leukocyte infiltration to the TME in solid cancers and contribute to immune evasion. Therefore, targeting the immunosuppressive TAMs and the cross-talk between them can be a promising strategy for improving anti-tumoral immune responses. This review aims to summarize the biology of TAMs, their recently identified roles in tumor development/angiogenesis, and recent advances in macrophage-based cancer immunotherapy approaches for treating cancers., (Copyright © 2021. Published by Elsevier Masson SAS.)

• Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal human malignancies due to the limited response to treatments. • The microenvironment of pancreatic cancer is full of immune cells and the immune system has a crucial role in the progression of PDAC. • Understanding the relation between immune cells and tumor cells is crucial to ponder for forthcoming therapeutic improvement. • Immunotherapy based approaches in pancreatic cancer can be employed as a novel strategy to obtain effective results in this cancer treatment. Pancreatic ductal adenocarcinoma has a poor 5-year survival rate that makes it one of the most fatal human malignancies. Unfortunately, despite the serious improvement in the survival of most cancers, there has been a minor advance in pancreatic cancer (PC). Major advances in PC treatment have been assessed over the bygone twenty-year time span, yet some complications make the survival of the patients shorter. Getting to know the PC tumor microenvironment (TME) and the immunosuppression that happens during the pathogenesis of this malignancy could be a great help to understand the nature of the immune system and find better treatment modalities based on it. Although many immune cells are present in PC, immunosuppression of the TME leads to severe immune dysfunction in the patients, therefore immune effectors fail to do their functions. Lately, immunotherapy has been presented as one of the promising treatment strategies for different malignancies including hepatocellular carcinoma, melanoma, non-small cell lung cancer, and kidney cancer. In PC, there has been shown promising results centered around the TME, immune checkpoint inhibitors, cancer vaccines, and other approaches especially when used as combinational therapy. Here we dig a little deeper into the role of the immune system and possible therapeutic options in the treatment of PC. [ABSTRACT FROM AUTHOR]

Although melanoma remains the deadliest skin cancer, the current treatment has not resulted in the desired outcomes. Unlike chemotherapy, immunotherapy has provided more tolerable approaches and revolutionized cancer therapy. Although dendritic cell-based vaccines have minor side effects, the undesirable response rates of traditional approaches have posed questions about their clinical translation. The immunosuppressive tumor microenvironment can be the underlying reason for their low response rates. Immune checkpoints and indoleamine 2,3-dioxygenase have been implicated in the induction of immunosuppressive tumor microenvironment. Growing evidence indicates that the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase/Protein kinase B (PKB) (PI3K/AKT) pathways, as the main oncogenic pathways of melanoma, can upregulate the tumoral immune checkpoints, like programmed death-ligand 1. This study briefly represents the main oncogenic pathways of melanoma and highlights the cross-talk between these oncogenic pathways with indoleamine 2,3-dioxygenase, tumoral immune checkpoints, and myeloid-derived suppressor cells. Moreover, this study sheds light on a novel tumor antigen on melanoma, which has substantial roles in tumoral immune checkpoints expression, indoleamine 2,3-dioxygenase secretion, and stimulating the oncogenic pathways. Finally, this review collects the lessons from the previous unsuccessful trials and integrates their lessons with new approaches in RNA-modified dendritic cell vaccines. Unlike traditional approaches, the advances in single-cell RNA-sequencing techniques and RNA-modified dendritic cell vaccines along with combined therapy of the immune checkpoint inhibitors, indoleamine 2,3-dioxygenase inhibitor, and RNA-modified dendritic cell-based vaccine can overcome these auto-inductive loops and pave the way for developing robust dendritic cell-based vaccines with the most favorable response rate and the least side effects. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is a clonal B‐cell malignancy characterized by the accumulation of neoplastic proliferation of a plasma cell in the bone marrow that produces a monoclonal immunoglobulin. The immune checkpoint inhibitors against programmed death‐1/programmed death‐1 ligand and cytotoxic T‐lymphocyte antigen 4 axis have demonstrated appropriate anticancer activity in several solid tumors and liquid cancers, and are rapidly transforming the practice of medical oncology. However, in a high percentage of patients, the efficacy of immune checkpoints blockade remains limited due to innate or primary resistance. Moreover, the malignancies progress in many patients due to acquired or secondary resistance, even after the clinical response to immune checkpoints' blockade. The evidence shows that multiple tumor‐intrinsic and tumor‐extrinsic factors and alterations in signaling pathways are involved in primary and secondary resistance to immune checkpoints blockade. Improved identification of intrinsic and extrinsic factors and mechanisms of resistance or response to immune checkpoints blockade may not only provide novel prognostic or predictive biomarkers but also guide the optimal combination/sequencing of immune checkpoint blockade therapy in the clinic. Here, we review the underlying biology and role of immune checkpoints blockade in patients with MM. Furthermore, we review the host and tumor‐related factor effects on immune checkpoints blockade in MM immunotherapy. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is still considered as the third most frequent cancer in the world. Microsatellite instability (MSI), inflammation, and microRNAs have been demonstrated as the main contributing factors in CRC. Subtype 1 CRC is defined by NK cells infiltration, induction of Th1 lymphocyte and cytotoxic T cell responses as well as upregulation of immune checkpoint proteins including programmed cell death‐1 (PD‐1). Based on the diverse features of CRC, such as the stage and localization of the tumor, several treatment approaches are available. However, the efficiency of these treatments may be decreased due to the development of diverse resistance mechanisms. It has been proven that monoclonal antibodies (mAbs) can increase the effectiveness of CRC treatments. Nowadays, several mAbs including nivolumab and pembrolizumab have been approved for the treatment of CRC. Immune checkpoint receptors including PD‐1 can be inhibited by these antibodies. Combination therapy gives an opportunity for advanced treatment for CRC patients. In this review, an update has been provided on the molecular mechanisms involved in MSI colorectal cancer immune microenvironment by focusing on PD‐ligand 1 (PD‐L1) and treatment of patients with advanced immunotherapy, which were examined in the different clinical trial phases. Considering induced expression of PD‐L1 by conventional chemotherapeutics, we have summarized the role of PD‐L1 in CRC, the chemotherapy effects on the PD‐1/PD‐L1 axis and novel combined approaches to enhance immunotherapy of CRC by focusing on PD‐L1. [ABSTRACT FROM AUTHOR]

Gastric cancer (GC), with a heterogeneous nature, is the third leading cause of death worldwide. Over the past few decades, stable reductions in the incidence of GC have been observed. However, due to the poor response to common treatments and late diagnosis, this cancer is still considered one of the lethal cancers. Emerging methods such as immunotherapy with immune checkpoint inhibitors (ICIs) have transformed the landscape of treatment for GC patients. There are presently eleven known members of the B7 family as immune checkpoint molecules: B7-1 (CD80), B7-2 (CD86), B7-H1 (PD-L1, CD274), B7-DC (PDCD1LG2, PD-L2, CD273), B7-H2 (B7RP1, ICOS-L, CD275), B7-H3 (CD276), B7-H4 (B7x, B7S1, Vtcn1), B7-H5 (VISTA, Gi24, DD1α, Dies1 SISP1), B7-H6 (NCR3LG1), B7-H7 (HHLA2), and Ig-like domain-containing receptor 2 (ILDR2). Interaction of the B7 family of immune-regulatory ligands with the corresponding receptors resulted in the induction and inhibition of T cell responses by sending co-stimulatory and co-inhibitory signals, respectively. Manipulation of the signals provided by the B7 family has significant potential in the management of GC. [ABSTRACT FROM AUTHOR]

The members of the B7 family, as immune checkpoint molecules, can substantially regulate immune responses. Since microRNAs (miRs) can regulate gene expression post-transcriptionally, we conducted a scoping review to summarize and discuss the regulatory cross-talk between miRs and new B7 family immune checkpoint molecules, i.e., B7-H3, B7-H4, B7-H5, butyrophilin like 2 (BTNL2), B7-H6, B7-H7, and immunoglobulin like domain containing receptor 2 (ILDR2). The current study was performed using a six-stage methodology structure and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline. PubMed, Embase, Scopus, Cochrane, ProQuest, and Google Scholar were systematically searched to obtain the relevant records to 5 November 2020. Two authors independently reviewed the obtained records and extracted the desired data. After quantitative and qualitative analyses, we used bioinformatics approaches to extend our knowledge about the regulatory cross-talk between miRs and the abovementioned B7 family members. Twenty-seven articles were identified that fulfilled the inclusion criteria. Studies with different designs reported gene–miR regulatory axes in various cancer and non-cancer diseases. The regulatory cross-talk between the aforementioned B7 family molecules and miRs might provide valuable insights into the pathogenesis of various human diseases. [ABSTRACT FROM AUTHOR]

Although the ever-increasing number of cancer patients pose substantial challenges worldwide, finding a treatment with the highest response rate and the lowest number of side effects is still undergoing research. Compared to chemotherapy, the relatively low side effects of cancer immunotherapy have provided ample opportunity for immunotherapy to become a promising approach for patients with malignancy. However, the clinical translation of immune-based therapies requires robust anti-tumoral immune responses. Immune checkpoints have substantial roles in the induction of an immunosuppressive tumor microenvironment and tolerance against tumor antigens. Identifying and targeting these inhibitory axes, which can be established between tumor cells and tumor-infiltrating lymphocytes, can facilitate the development of anti-tumoral immune responses. Bispecific T-cell engagers, which can attract lymphocytes to the tumor microenvironment, have also paved the road for immunological-based tumor elimination. The development of CAR-T cells and their gene editing have brought ample opportunity to recognize tumor antigens, independent from immune checkpoints and the major histocompatibility complex (MHC). Indeed, there have been remarkable advances in developing various CAR-T cells to target tumoral cells. Knockout of immune checkpoints via gene editing in CAR-T cells might be designated for a breakthrough for patients with malignancy. In the midst of this fast progress in cancer immunotherapies, there is a need to provide up-to-date information regarding immune checkpoints, bispecific T-cell engagers, and CAR-T cells. Therefore, this review aims to provide recent findings of immune checkpoints, bispecific T-cell engagers, and CAR-T cells in cancer immunotherapy and discuss the pertained clinical trials. [ABSTRACT FROM AUTHOR]

• There is a positive correlation between VISTA and CTLA-4 expression in Luminal A breast cancers. • Combined tumor-intrinsic VISTA/CTLA-4 knockdown increases T-cells' pro-inflammatory factors. • Combined tumor-intrinsic VISTA/CTLA-4 knockdown decreases MCF-7 stemness and cell cycle. • Combined tumor-intrinsic VISTA/CTLA-4 knockdown decreases MCF-7 cell migration. As inhibitory immune checkpoint molecules, cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and V-domain Ig suppressor of T-cell activation (VISTA) can be expressed in tumoral cells and facilitate immune evasion of tumoral cells. Herein, we studied the significance of tumor-intrinsic CTLA-4 and VISTA silencing in tumor development and inflammatory factors expression in a co-culture system with MCF7 and T-cells. MCF7 cells were transfected with 60 pmol of CTLA-siRNA, VISTA-siRNA, and dual VISTA-/CTLA-4-siRNA. The MTT assay was performed to study the effect of CTLA-4 and VISTA knockdown on the viability of MCF7 cells. Colony formation and wound-healing assays were performed to investigate the effect of CTLA-4 and VISTA silencing on the clonogenicity and migration of MCF7 cells. Flow cytometry was used to study the significance of CTLA-4 and VISTA knockdown on the apoptosis and cell cycle of MCF7 cells. Also, a co-culture system with MCF7 and T-cells was developed to study the expression levels of IL-2, IFN-γ, TNF-α, TGF-β, and IL-10 following CTLA-4 and VISTA knockdown. The expression levels of caspase3, Bax, Bcl2, and MMP-9 were also investigated using quantitative real-time PCR. Finally, the TCGA Breast Cancer and GSE45827 datasets were analyzed to study the potential prognostic values of VISTA and CTLA-4, their expression difference in luminal A breast cancer and non-tumoral tissues, and their correlation in luminal A breast cancer tissues. Combined knockdown of tumor-intrinsic VISTA and CTLA-4 is superior in upregulating IL-2, IFN-γ, and TNF-α, downregulating TGF-β and IL-10 in T lymphocytes. Also, the combined silencing arrests the cell cycle at the sub-G1 phase, decreases migration, inhibits clonogenicity, and reduces cell viability of MCF7 cells. This combined treatment upregulates caspase 9 and BAX and downregulates MMP-9 in MCF7 cells. Our in-silico results have demonstrated a significant positive correlation between CTLA-4 and VISTA in luminal A breast cancer. The additive effect of the combined knockdown of tumor-intrinsic VISTA and CTLA-4 can substantially upregulate pro-inflammatory factors, downregulate anti-inflammatory factors, and inhibit tumor development in MCF7 cells. The significant positive correlation between VISTA and CTLA-4 in luminal A breast cancer might support the idea that a network of inhibitory immune checkpoint molecules regulates anti-tumoral immune responses; thus, combinational immune checkpoint molecules blockade can be suggested. [ABSTRACT FROM AUTHOR]

Immunotherapy is a promising field, which enhances and harnesses the powers of the host immune system against cancer and in recent years, has become a major application of the fundamental research of cancer immunology. Cancer immunotherapy is often more targeted than non-specific therapy approaches, including radiotherapy or chemotherapy, as the immune system can be trained to remember cancer cells, highlighting a durable approach that can be maintained after the treatment completion. Immunotherapy functions by directing the immune system to attack the tumour cells via targeting tumour antigens, also enhancing the existing anti-tumour immune responses. Current strategies include non-specific immunotherapy, cancer vaccines, oncolytic virus therapy, monoclonal antibodies, immune checkpoints and T cell therapy. The combination of effective approaches can increase the immunotherapy efficacy, leading to durable anti-tumour immune responses. This review will discuss the immunotherapy approaches, particularly immune checkpoints and T cell therapy, which are the most common clinical applications in cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Dendritic cells (DCs) can present tumoral antigens to T-cells and stimulate T-cell-mediated anti-tumoral immune responses. In addition to uptaking, processing, and presenting tumoral antigens to T-cells, co-stimulatory signals have to be established between DCs with T-cells to develop anti-tumoral immune responses. However, most of the tumor-infiltrated immune cells are immunosuppressive in the tumor microenvironment (TME), paving the way for immune evasion of tumor cells. This immunosuppressive TME has also been implicated in suppressing the DC-mediated anti-tumoral immune responses, as well. Various factors, i.e., immunoregulatory cells, metabolic factors, tumor-derived immunosuppressive factors, and inhibitory immune checkpoint molecules, have been implicated in developing the immunosuppressive TME. Herein, we aimed to review the biology of DCs in developing T-cell-mediated anti-tumoral immune responses, the significance of immunoregulatory cells in the TME, metabolic barriers contributing to DCs dysfunction in the TME, tumor-derived immunosuppressive factors, and inhibitory immune checkpoint molecules in DC-based cell therapy outcomes. With reviewing the ongoing clinical trials, we also proposed a novel therapeutic strategy to increase the efficacy of DC-based cell therapy. Indeed, the combination of DC-based cell therapy with monoclonal antibodies against novel immune checkpoint molecules can be a promising strategy to increase the response rate of patients with cancers. The immune checkpoint molecules play a critical role in the dendritic cell dysfunction and decrease the efficacy of dendritic cell-based anti-cancer immunotherapies. Therefore, the development of combination therapies such as the use of immune checkpoint inhibitors along with dendritic cell vaccines can be considered as a promising strategy to fight cancer. [Display omitted] • Immunosuppressive TME inhibits DCs' activity in inducing anti-tumoral T cell responses. • Immune checkpoints expression on DCs is one of the major causes of DCs dysfunction in the TME. • Combination therapy with ICIs improves the efficiency of DC-based therapy. • ICIs combination therapy with DC-based therapeutics are evaluating in numerous clinical trials. [ABSTRACT FROM AUTHOR]

The growth and development of cancer are directly correlated to the suppression of the immune system. A major breakthrough in cancer immunotherapy depends on various mechanisms to detect immunosuppressive factors that inhibit anti-tumor immune responses. Immune checkpoints are expressed on many immune cells such as T-cells, regulatory B cells (Bregs), dendritic cells (DCs), natural killer cells (NKs), regulatory T (Tregs), M2-type macrophages, and myeloid-derived suppressor cells (MDSCs). Immune inhibitory molecules, including CTLA-4, TIM-3, TIGIT, PD-1, and LAG-3, normally inhibit immune responses via negatively regulating immune cell signaling pathways to prevent immune injury. However, the up-regulation of inhibitory immune checkpoints during tumor progression on immune cells suppresses anti-tumor immune responses and promotes immune escape in cancer. It has recently been indicated that cancer cells can up-regulate various pathways of the immune checkpoints. Therefore, targeting immune inhibitory molecules through antibodies or miRNAs is a promising therapeutic strategy and shows favorable results. Immune checkpoint inhibitors (ICIs) are introduced as a new immunotherapy strategy that enhance immune cell-induced antitumor responses in many patients. In this review, we highlighted the function of each immune checkpoint on different immune cells and therapeutic strategies aimed at using monoclonal antibodies and miRNAs against inhibitory receptors. We also discussed current challenges and future strategies for maximizing these FDA-approved immunosuppressants' effectiveness and clinical success in cancer treatment. [Display omitted] • Inhibitory immune checkpoints are the primary cause of immune cells dysfunction. • Elevated levels of inhibitory immune checkpoints on immune cells induce tumor immune escape. • The utilization of immune checkpoint inhibitor (ICI) therapy assists cancer treatment. • ICI, in combination with other cancer treatment approaches, promotes the immune response rate. • The miRNAs control the antitumor response by regulating inhibitory immune checkpoints. [ABSTRACT FROM AUTHOR]

Despite considerable progressions, cardiovascular disease (CVD) is still one of the major causes of mortality around the world, indicates an important and unmet clinical need. Recently, extensive studies have been performed on the role of inflammatory factors as either a major or surrogate factor in the pathophysiology of CVD. Epidemiological observations suggest the theory of the role of inflammatory mediators in the development of cardiovascular events. This may support the idea that targeted anti-inflammatory therapies, on the background of traditional validated medical therapies, can play a significant role in prevention and even reduction of cardiovascular disorders. Many randomized controlled trials have shown that drugs commonly useful for primary and secondary prevention of CVD have an anti-inflammatory mechanism. Further, many anti-inflammatory drugs are being examined because of their potential to reduce the risk of cardiovascular problems. In this study, we review the process of inflammation in the development of cardiovascular events, both in vivo and clinical evidence in immunotherapy for CVD. Unlabelled Image [ABSTRACT FROM AUTHOR]