Many immunostimulants act as vaccine adjuvants via activation of the innate immune system, although in many cases it is unclear which specific molecules contribute to the stimulatory activity. QS-21 ...is a defined, highly purified, and soluble saponin adjuvant currently used in licensed and exploratory vaccines, including vaccines against malaria, cancer, and HIV-1. However, little is known about the mechanisms of cellular activation induced by QS-21. We observed QS-21 to elicit caspase-1-dependent IL-1β and IL-18 release in antigen-presenting cells such as macrophages and dendritic cells when co-stimulated with the TLR4-agonist adjuvant monophosphoryl lipid A. Furthermore, our data suggest that the ASC-NLRP3 inflammasome is responsible for QS-21-induced IL-1β/IL-18 release. At higher concentrations, QS-21 induced macrophage and dendritic cell death in a caspase-1-, ASC-, and NLRP3-independent manner, whereas the presence of cholesterol rescued cell viability. A nanoparticulate adjuvant that contains QS-21 as part of a heterogeneous mixture of saponins also induced IL-1β in an NLRP3-dependent manner. Interestingly, despite the role NLRP3 plays for cellular activation in vitro, NLRP3-deficient mice immunized with HIV-1 gp120 and QS-21 showed significantly higher levels of Th1 and Th2 antigen-specific T cell responses and increased IgG1 and IgG2c compared with wild type controls. Thus, we have identified QS-21 as a nonparticulate single molecular saponin that activates the NLRP3 inflammasome, but this signaling pathway may contribute to decreased antigen-specific responses in vivo.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Traditional views of the inflammasome highlight the assembly of pre-existing core components shortly after infection or tissue damage. Emerging work, however, suggests that the inflammasome machinery ...is also subject to 'tunable' or inducible signals that might accelerate its autocatalytic properties and dictate where inflammasome assembly takes place in the cell. Many of these signals operate downstream of interferon receptors to elicit inflammasome regulators, including a new family of interferon-induced GTPases called 'guanylate-binding proteins' (GBPs). Here we investigate the critical roles of interferon-induced GBPs in directing inflammasome subtype-specific responses and their consequences for cell-autonomous immunity to a wide variety of microbial pathogens. We discuss emerging mechanisms of action and the potential effect of these GBPs on predisposition to sepsis and other infectious or inflammatory diseases.
Asthma is a major respiratory disorder characterised by chronic inflammation and airway remodelling. It affects about 1–8% of the global population and is responsible for over 461,000 deaths ...annually. Until recently, the pharmacotherapy of severe asthma involved high doses of inhaled corticosteroids in combination with β-agonist for prolonged action, including theophylline, leukotriene antagonist or anticholinergic yielding limited benefit. Although the use of newer agents to target Th2 asthma endotypes has improved therapeutic outcomes in severe asthmatic conditions, there seems to be a paucity of understanding the diverse mechanisms through which these classes of drugs act. This article delineates the molecular and immunomodulatory mechanisms of action of new antiasthmatic agents currently being trialled in preclinical and clinical studies to remit asthmatic conditions. The ultimate goal in developing antiasthmatic agents is based on two types of approaches: either anti-inflammatory or bronchodilators. Biologic and most small molecules have been shown to modulate specific asthma endotypes, targeting thymic stromal lymphopoietin, tryptase, spleen tyrosine kinase (Syk), Janus kinase, PD-L1/PD-L2, GATA-3, and CD38 for the treatment and management of Th2 endotype asthma.
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•Biologics and small molecules are increasingly recognised for their great potential in the pharmacotherapy of asthma.•These agents may be beneficial in severe asthma as well as mitigating the progression of acute to severe asthma.•Understanding the mechanism of action of new target agents is relevant in pharmacology.•TSLP, tryptase, Syk, janus kinase, PD-L1/PD-L2, GATA-3, and CD38 are important targets in Th2 asthma endotype.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Lung cancer is the most common cause of cancer-related deaths. Lung cancers can be classified as small-cell (SCLC) or non-small cell (NSCLC). About 84% of all lung cancers are NSCLC and about 16% are ...SCLC. For the past few years, there have been a lot of new advances in the management of NSCLC in terms of screening, diagnosis and treatment. Unfortunately, most of the NSCLCs are resistant to current treatments and eventually progress to advanced stages. In this perspective, we discuss some of the drugs that can be repurposed to specifically target the inflammatory pathway of NSCLC utilizing its well-defined inflammatory tumor microenvironment. Continuous inflammatory conditions are responsible to induce DNA damage and enhance cell division rate in lung tissues. There are existing anti-inflammatory drugs which were found suitable for repurposing in non-small cell lung carcinoma (NSCLC) treatment and drug modification for delivery via inhalation. Repurposing anti-inflammatory drugs and their delivery through the airway is a promising strategy to treat NSCLC. In this review, suitable drug candidates that can be repurposed to treat inflammation-mediated NSCLC will be comprehensively discussed together with their administration via inhalation from physico-chemical and nanocarrier perspectives.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Immunotherapies have revolutionized cancer treatment. In particular, immune checkpoint therapy (ICT) leads to durable responses in some patients with some cancers. However, the majority of treated ...patients do not respond. Understanding immune mechanisms that underlie responsiveness to ICT will help identify predictive biomarkers of response and develop treatments to convert non-responding patients to responding ones. ICT primarily acts at the level of adaptive immunity. The specificity of adaptive immune cells, such as T and B cells, is determined by antigen-specific receptors. T cell repertoires can be comprehensively profiled by high-throughput sequencing at the bulk and single-cell level. T cell receptor (TCR) sequencing allows for sensitive tracking of dynamic changes in antigen-specific T cells at the clonal level, giving unprecedented insight into the mechanisms by which ICT alters T cell responses. Here, we review how the repertoire influences response to ICT and conversely how ICT affects repertoire diversity. We will also explore how changes to the repertoire in different anatomical locations can better correlate and perhaps predict treatment outcome. We discuss the advantages and limitations of current metrics used to characterize and represent TCR repertoire diversity. Discovery of predictive biomarkers could lie in novel analysis approaches, such as network analysis of amino acids similarities between TCR sequences. Single-cell sequencing is a breakthrough technology that can link phenotype with specificity, identifying T cell clones that are crucial for successful ICT. The field of immuno-sequencing is rapidly developing and cross-disciplinary efforts are required to maximize the analysis, application, and validation of sequencing data. Unravelling the dynamic behavior of the TCR repertoire during ICT will be highly valuable for tracking and understanding anti-tumor immunity, biomarker discovery, and ultimately for the development of novel strategies to improve patient outcomes.
The total number of cumulative cases and deaths from the COVID-19 pandemic caused by SARS-CoV-2 is still increasing worldwide. Although many countries have actively implemented vaccination strategies ...to curb the epidemic, there is no specific efficient therapeutic drug for this virus to effectively reduce deaths. Therefore, the underappreciated macromolecular compounds have become the spotlight of research. Furthermore, the medicinal compounds in plants that provide myriad possibilities to treat human diseases have become of utmost importance. Experience indicates that Traditional Chinese medicine effectively treats SARS and has been used for treating patients with COVID-19 in China. As one of the world’s oldest herbal remedies, licorice is used for treating patients with all stages of COVID-19. Glycyrrhizic acid (GA), the main active compound in licorice, has been proven effective in killing the SARS virus. Meanwhile, as a natural plant molecule, GA can also directly target important protein structures of the SARS-CoV-2 virus and inhibit the replication of SARS-CoV-2. In this review, we summarized the immune synergy of GA and its potential role in treating COVID-19 complications. Besides, we reviewed its anti-inflammatory effects on the immune system and its positive effects in cooperation with various drugs to fight against COVID-19 and its comorbidities. The purpose of this review is to elucidate and suggest that GA can be used as a potential drug during COVID-19 treatment.
Although less common, melanoma is the deadliest form of skin cancer largely due to its highly metastatic nature. Currently, there are limited treatment options for metastatic melanoma and many of ...them could cause serious side effects. A better understanding of the molecular mechanisms underlying the complex disease pathophysiology of metastatic melanoma may lead to the identification of novel therapeutic targets and facilitate the development of targeted therapeutics. In this study, we investigated the role of leucine-rich α-2-glycoprotein 1 (LRG1) in melanoma development and progression. We first established the association between LRG1 and melanoma in both human patient biopsies and mouse melanoma cell lines and revealed a significant induction of LRG1 expression in metastatic melanoma cells. We then showed no change in tumour cell growth, proliferation, and angiogenesis in the absence of the host
. On the other hand, there was reduced melanoma cell metastasis to the lungs in
-deficient mice. This observation was supported by the promoting effect of LRG1 in melanoma cell migration, invasion, and adhesion. Mechanistically, LRG1 mediates melanoma cell invasiveness in an EGFR/STAT3-dependent manner. Taken together, our studies provided compelling evidence that LRG1 is required for melanoma metastasis but not growth. Targeting LRG1 may offer an alternative strategy to control malignant melanoma.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Pancreatic cancer is a fatal malignant neoplasm with infrequent signs and symptoms until a progressive stage. In 2020, GLOBOCAN reported that pancreatic cancer accounts for 4.7% of all cancer deaths. ...Despite the availability of standard chemotherapy regimens for treatment, the survival benefits are not guaranteed because tumor cells become chemoresistant even due to the development of chemoresistance in tumor cells even with a short treatment course, where apoptosis and autophagy play critical roles.
This review compiled essential information on the regulatory mechanisms and roles of apoptosis and autophagy in pancreatic cancer, as well as drug-like molecules that target different pathways in pancreatic cancer eradication, with an aim to provide ideas to the scientific communities in discovering novel and specific drugs to treat pancreatic cancer, specifically PDAC.
Electronic databases that were searched for research articles for this review were Scopus, Science Direct, PubMed, Springer Link, and Google Scholar. The published studies were identified and retrieved using selected keywords.
Many small-molecule anticancer agents have been developed to regulate autophagy and apoptosis associated with pancreatic cancer treatment, where most of them target apoptosis directly through EGFR/Ras/Raf/MAPK and PI3K/Akt/mTOR pathways. The cancer drugs that regulate autophagy in treating cancer can be categorized into three groups: i) direct autophagy inducers (e.g., rapamycin), ii) indirect autophagy inducers (e.g., resveratrol), and iii) autophagy inhibitors. Resveratrol persuades both apoptosis and autophagy with a cytoprotective effect, while autophagy inhibitors (e.g., 3-methyladenine, chloroquine) can turn off the protective autophagic effect for therapeutic benefits. Several studies showed that autophagy inhibition resulted in a synergistic effect with chemotherapy (e.g., a combination of metformin with gemcitabine/ 5FU). Such drugs possess a unique clinical value in treating pancreatic cancer as well as other autophagy-dependent carcinomas.
Previous studies have indicated a synergistic effect between radiotherapy and immunotherapy. A better understanding of how this combination affects the immune system can help to clarify its role in ...the treatment of metastatic cancer. We performed T cell receptor (TCR) sequencing on 46 sequentially collected samples from 15 patients with stage IV non‐small cell lung cancer, receiving stereotactic body radiotherapy combined with a programmed cell death ligand‐1 (PD‐L1) inhibitor. TCR repertoire diversity was assessed using Rényi diversity curves and the Shannon diversity index. TCR clones were tracked over time. We found decreasing or stable diversity in the best responders, and an increase in diversity at progression in patients with an initial response. Expansion of TCR clones was more often seen in responders. Several patients also developed new clones of high abundance. This seemed to be more related to radiotherapy than to immune checkpoint blockade. In summary, we observed similar dynamics in the TCR repertoire as have been described with immunotherapy alone. In addition, the occurrence of new unique clones of high abundance after radiotherapy may indicate that radiotherapy functions as a personalized cancer vaccine.
Radiotherapy and immunotherapy have been proposed to work synergistically in the treatment of cancer. We used T cell receptor (TCR) sequencing to monitor the immunological response to combined stereotactic radiotherapy and PD‐L1 blockade in patients with metastatic non‐small cell lung cancer. Specifically, we investigated possible mechanisms of action and the potential of the TCR repertoire as a dynamic biomarker.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Immune checkpoint therapy (ICT) results in durable responses in individuals with some cancers, but not all patients respond to treatment. ICT improves CD8
cytotoxic T lymphocyte (CTL) function, but ...changes in tumor antigen-specific CTLs post-ICT that correlate with successful responses have not been well characterized. Here, we studied murine tumor models with dichotomous responses to ICT. We tracked tumor antigen-specific CTL frequencies and phenotype before and after ICT in responding and non-responding animals. Tumor antigen-specific CTLs increased within tumor and draining lymph nodes after ICT, and exhibited an effector memory-like phenotype, expressing IL-7R (CD127), KLRG1, T-bet, and granzyme B. Responding tumors exhibited higher infiltration of effector memory tumor antigen-specific CTLs, but lower frequencies of regulatory T cells compared to non-responders. Tumor antigen-specific CTLs persisted in responding animals and formed memory responses against tumor antigens. Our results suggest that increased effector memory tumor antigen-specific CTLs, in the presence of reduced immunosuppression within tumors is part of a successful ICT response. Temporal and nuanced analysis of T cell subsets provides a potential new source of immune based biomarkers for response to ICT.
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