Immunotherapeutics targeting immune checkpoint receptors or their ligands (i.e., immune checkpoint inhibitors), have been groundbreaking in the field of oncology, radically changing the approach to treatment and improving the clinical outcomes of an ever-expanding list of solid tumors and hematological malignancies. However, immune checkpoint inhibitors (ICI) are not devoid of side effects, collectively regarded as immune-related adverse events (irAE); they are not easily uncovered in preclinical immunotoxicological investigations and are often due to the very low expression of their targets in immunologically-unchallenged non-clinical species. We have characterized expression of a broad range of immune checkpoint receptors in peripheral blood mononuclear cell (PBMC) subpopulations from cynomolgus monkeys and healthy human volunteers, under resting and T-cell stimulatory conditions by multicolor flow cytometry to inform appropriate species selection for modeling potential irAE in immunotherapeutic preclinical research. Focusing on the response of the main lymphocyte populations to interleukin (IL)-2 alone, or in combination with anti-CD3 and anti-CD28 antibodies, checkpoints with shared similarities and key differences between the two species were identified. The results of this first study provide a database for the expression and response to stimulation for immune checkpoint receptors and can help guide future model selection in the design of preclinical studies involving immunotherapeutics directed against these targets.

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality, with limited treatment options at advanced stages. The gut microbiota, a diverse community of microorganisms residing in the gastrointestinal tract, plays a pivotal role in regulating immune responses through the gut-liver axis. Emerging evidence underscores its impact on HCC progression and the efficacy of immunotherapy. This review explores the intricate interactions between gut microbiota and the immune system in HCC, with a focus on key immune cells and pathways involved in tumor immunity. Additionally, it highlights strategies for modulating the gut microbiota - such as fecal microbiota transplantation, dietary interventions, and probiotics - as potential approaches to enhancing immunotherapy outcomes. A deeper understanding of these mechanisms could pave the way for novel therapeutic strategies aimed at improving patient prognosis.

Programmed cell death protein 1 (PD-1) is a critical immune checkpoint receptor that suppresses immune responses largely through its interaction with PD-L1. Tumors exploit this mechanism to evade immune surveillance, positioning immune checkpoint inhibitors targeting the PD-1/PD-L1 axis as groundbreaking advancements in cancer therapy. However, the overall effectiveness of these therapies is often constrained by an incomplete understanding of the underlying mechanisms. Recent research has uncovered the pivotal role of various post-translational modifications (PTMs) of PD-1, including ubiquitination, UFMylation, phosphorylation, palmitoylation, and glycosylation, in regulating its protein stability, localization, and protein-protein interactions. As much, dysregulation of these PTMs can drive PD-1-mediated immune evasion and contribute to therapeutic resistance. Notably, targeting PD-1 PTMs with small-molecule inhibitors or monoclonal antibodies (MAbs) has shown potential to bolster anti-tumor immunity in both pre-clinical mouse models and clinical trials. This review highlights recent findings on PD-1's PTMs and explores emerging therapeutic strategies aimed at modulating these modifications. By integrating these mechanistic insights, the development of combination cancer immunotherapies can be further rationally advanced, offering new avenues for more effective and durable treatments.

Chronic pain has substantial effects on patients' quality of life and psychological well-being. It does not respond satisfactorily to available medicinal therapeutics because its mechanism remains unclear. Recent studies have shown a strong relationship between chronic pain and immunomodulation. As important members of the immune response, CD28 superfamily costimulatory molecules were demonstrated to have an analgesic effect on chronic pain. Based on research on the role of these molecules in chronic pain, new and highly effective analgesic medicines are anticipated that could be used in combination with some previous analgesic medicines to reduce substance abuse and side effects. This review of the literature will examine the pain-regulating mechanisms of CD28 superfamily costimulatory molecules, focusing on immunomodulation. In addition, this review will discuss the potential and difficulties of developing novel analgesic medicines targeting CD28 superfamily costimulatory molecules.

Cancer is a leading cause of death globally, with resistance to therapy representing a major obstacle to effective treatment. The tumor microenvironment (TME), comprising a complex network to cellular and non-cellular components including cancer-associated fibroblasts, immune cells, the extracellular matrix and region of hypoxia, is integral to cancer progression and therapeutic resistance. This review delves into the multifaceted interactions within the TME that contribute to tumor growth, survival and immune evasion. Key elements such as the role of cancer- associated fibroblasts in remodeling the extracellular matrix and promoting angiogenesis, the influence of immune cells such as tumor-associated macrophages in creating an immunosuppressive milieu and the impact of hypoxia conditions on metabolic adaptation and therapy resistance are thoroughly examined. This review evaluates current and emerging TME-targeted therapeutic strategies, including inhibitors of extracellular matrix components, modulators of immune cell activity and approached to alleviate hypoxia. Combination therapies that integrate TME-targeted agents with conventional treatments such as chemotherapy and immunotherapy are also discussed for their potential to enhance treatment efficacy and circumvent resistance mechanisms. By synthesising recent advances in TME research and therapeutic innovation, this paper aims to underscore the importance of TME in cancer therapy and highlight promising avenues for improving patient outcomes through targeted intervention.

Hypertensive nephrosclerosis (HN) is a major cause of end-stage renal disease; however, few longitudinal studies have employed serum proteomics to document its progression. This study aimed to identify potential circulating biomarkers indicative of disease progression in HN by performing serum proteomic analysis at two time points in patients with progressive and stable disease.

Forty-one patients diagnosed with HN were recruited from the UK Salford Kidney Study, with serum samples collected at baseline and follow-up (1.5-10 years after baseline). Twenty-five patients experienced stable disease course, while 16 patients experienced progressive disease. Proteomics was performed via tandem mass tag labelling and liquid chromatography-tandem mass-spectrometry (LC-MS). Pathway analysis was performed on all significantly abundant proteins, as was network analysis of circulating proteins that are abundant in the kidney according to the Human Protein Atlas.

Pathway analysis revealed significant enrichment in pathways related to inflammation and infection, including complement and coagulation cascades, as well as metabolic processes in patients with disease progression. Marker abundance levels related to adhesion and the ECM were also altered in progresssive disease follow-up, compared to stable disease follow-up.

The observed changes in inflammatory and adhesion-related pathways may offer valuable insights into the mechanisms driving HN progression and potential targets for intervention.

Pancreatic cancer is a highly aggressive and lethal disease, characterized by a limited response to chemotherapy and overall poor prognosis. Pancreatic cancers with a distinct mismatch repair deficiency, although relatively rare, have been shown to be associated with markedly better outcomes in comparison. Furthermore, whereas pancreatic cancers are generally unresponsive to current immunotherapy, this specific group of tumors has been shown to have a notable susceptibility to immune checkpoint inhibitors.

In this review, we aim to summarize the relevant literature regarding mismatch-repair associated pancreatic cancers, the impacted biological mechanisms, and the resulting vulnerabilities for potential opportunistic immunotherapeutic treatment approaches. We will also review the current clinical studies assessing survival outcomes of mismatch repair deficient pancreatic cancers and ongoing clinical trials in this emerging field.

Patients with dMMR/MSI-H pancreatic cancers harbor a distinct phenotype that has increased immune activation, greater responsiveness to immune checkpoint inhibitor therapy and better overall survival when compared to other pancreatic cancers. Although this molecular subtype makes up a small minority of cases, emerging data suggest immunotherapy may offer benefit to these patients.

Immunotherapy emerges as a promising approach, marked by recent substantial progress in elucidating how the host immune response impacts tumor development and its sensitivity to various treatments. Immune checkpoint inhibitors have revolutionized cancer therapy by unleashing the power of the immune system to recognize and eradicate tumor cells. Among these, inhibitors targeting the programmed cell death protein 1 (PD-1) and its ligand (PD-L1) have garnered significant attention due to their remarkable clinical efficacy across various malignancies. This review delves into the mechanisms of action, clinical applications, and emerging therapeutic strategies surrounding PD-1/PD-L1 blockade. We explore the intricate interactions between PD-1/PD-L1 and other immune checkpoints, shedding light on combinatorial approaches to enhance treatment outcomes and overcome resistance mechanisms. Furthermore, we discuss the expanding landscape of immune checkpoint inhibitors beyond PD-1/PD-L1, including novel targets such as CTLA-4, LAG-3, TIM-3, and TIGIT. Through a comprehensive analysis of preclinical and clinical studies, we highlight the promise and challenges of immune checkpoint blockade in cancer immunotherapy, paving the way for future advancements in the field.

Chemical ligand binding to PD-1 is a powerful approach for studying protein-protein interactions and advancing immunotherapy. In this study, we introduce a novel II peptide with strong binding affinity for PD-1. Molecular docking analysis reveals key interactions between the II peptide and PD-1, supporting inhibition ELISA data and indicating that the II peptide overlaps with the PD-1/PD-L1 interaction interface.

Host immune responses to antigens are tightly regulated through the activation and inhibition of synergistic signaling networks that maintain homeostasis. Stimulatory checkpoint molecules initiate attacks on infected or tumor cells, while inhibitory molecules halt the immune response to prevent overreaction and self-injury. Multiple immune checkpoint proteins are grouped into families based on common structural domains or origins, yet the variability within and between these families remains largely unexplored. In this review, we discuss the current understanding of the mechanisms underlying the co-suppressive functions of CTLA-4, PD-1, and other prominent immune checkpoint pathways. Additionally, we examine the IgSF, PVR, TIM, SIRP, and TNF families, including key members such as TIGIT, LAG-3, VISTA, TIM-3, SIRPα, and OX40. We also highlight the unique dual role of VISTA and SIRPα in modulating immune responses under specific conditions, and explore potential immunotherapeutic pathways tailored to the distinct characteristics of different immune checkpoint proteins. These insights into the unique advantages of checkpoint proteins provide new directions for drug discovery, emphasizing that emerging immune checkpoint molecules could serve as targets for novel therapies in cancer, autoimmune diseases, infectious diseases, and transplant rejection.

Programmed cell death protein 1 (PD-1) is frequently detected in certain subsets of tumor cells, and our understanding of PD-1 signaling consequences has expanded to include control of tumor growth, stemness and drug resistance. Nonetheless, tumor cell-intrinsic PD-1 has been comparatively underexplored in relation to PD-1 expressed on the surface of immune cells as an immune checkpoint, despite the imperative need to comprehensively elucidate the underlying mechanisms of action for achieving optimal responses in tumor immunotherapy. Here, we review the roles of the regulation and function of tumor-intrinsic PD-1 from its expression to degradation processes. Our primary focus is on unraveling its enigmatic influence on tumorigenesis and progression as proposed by recent findings, while navigating the labyrinthine network of regulatory mechanisms governing its expression and intricate functional interplay. We also discuss how the elucidation of the mechanistic underpinnings of tumor-intrinsic PD-1 expression holds the potential to explain the divergent therapeutic outcomes observed with anti-PD-1-based combination therapies, thereby furnishing indispensable insights crucial for synergistic anti-tumor strategies.

Chinese herbal medicines have played a significant role in the development of new and effective drugs, but how to identify the active ingredients from complex extracts of traditional Chinese herbal medicines was a research difficulty. In recent years, few studies have focused on high-efficiency identification of small-molecule inhibitors of Programmed Death Ligand 1 with lower antigenicity and flexible structure tunability. In order to identify small molecule inhibitors of PD-L1 from complex Chinese herbal extracts, this study established a protein-ligand trapping system based on high-performance liquid chromatography coupled with a photo-diode array detector, ion trap/quadrupole time-of-flight tandem mass spectrometry, and a Programmed Death Ligand 1 affinity chromatography unit (ACPD-L1-HPLC-PDA-IT-TOF (Q-TOF)-MS) to rapidly screen and identify small-molecule inhibitors of Programmed Death Ligand 1 from Toddalia asiatica (L.) Lam. Fourteen components were then identified as PD-L1 binders, and surface plasmon resonance (SPR) validation results showed that six of them-magnoflorine (6), nitidine (22), chelerythrine (24), jatrorrhizine (13), toddaculin (68), and toddanol (45)-displayed PD-L1 binding activity. Laser scanning confocal microscopy results demonstrated that these compounds effectively inhibited the binding of PD-1 to PD-L1 in a dose-dependent manner. Additionally, flow cytometry analysis indicated they could promote human lung cancer cell line (A549) apoptosis when co-cultured with Peripheral Blood Mononuclear Cells (PBMCs). The system's innovation lies in its first integration of dynamic protein-ligand trapping with multi-dimensional validation, coupled with high-throughput screening capacity for structurally diverse natural products. This workflow overcomes traditional phytochemical screening bottlenecks by preserving native protein conformations during affinity capture while maintaining chromatographic resolution, offering a transformative template for accelerating natural product-derived immunotherapeutics through the PD-1/PD-L1 pathway.

Immune checkpoints, such as PD-1 and CTLA-4, are crucial regulators of immune responses, acting as gatekeepers to balance immunity against foreign antigens and self-tolerance. These checkpoints play a key role in maintaining cardiac homeostasis by preventing immune-mediated damage to critical organs like the heart. In this study, we explored the involvement of PD-1 and CTLA-4 in cardiovascular complications, particularly atherosclerosis and myocarditis, which can lead to heart failure. We conducted a comprehensive analysis using animal models and clinical data to assess the effects of immune checkpoint inhibition on cardiac function. Our findings indicate that disruption of PD-1 and CTLA-4 pathways exacerbates myocardial inflammation, accelerates atherosclerotic plaque formation, and promotes the development of heart failure. Additionally, we observed that immune checkpoint inhibition in these models led to increased infiltration of T lymphocytes, higher levels of pro-inflammatory cytokines, and enhanced tissue damage. These results suggest that PD-1 and CTLA-4 are critical in preserving cardiac health, and their inhibition can result in severe cardiovascular toxicity. Our study emphasizes the need for careful monitoring of cardiovascular health in patients undergoing immune checkpoint inhibitor therapies.

The immune composition of solid tumors is typically inferred from biomarkers, such as histologic and molecular classifications, somatic mutational burden, and PD-L1 expression. However, the extent to which these biomarkers predict the immune landscape in gastric adenocarcinoma-an aggressive cancer often linked to chronic inflammation-remains poorly understood. We leveraged high-dimensional spectral cytometry to generate a comprehensive single-cell immune landscape of tumors, normal tissue, and lymph nodes from patients in the Western Hemisphere with gastric adenocarcinoma. The immune composition of gastric tumors could not be predicted by traditional metrics such as tumor histology, molecular classification, mutational burden, or PD-L1 expression via IHC. Instead, our findings revealed that innate immune surveillance within tumors could be anticipated by the immune profile of the normal gastric mucosa. Additionally, distinct T-cell states in the lymph nodes were linked to the accumulation of activated and memory-like CD8+ tumor-infiltrating lymphocytes. Unbiased reclassification of patients based on tumor-specific immune infiltrate generated four distinct subtypes with varying immune compositions. Tumors with a T cell-dominant immune subtype, which spanned The Cancer Genome Atlas molecular subtypes, were exclusively associated with superior responses to immunotherapy. Parallel analysis of metastatic gastric cancer patients treated with immune checkpoint blockade showed that patients who responded to immunotherapy had a pretreatment tumor composition that corresponded to a T cell-dominant immune subtype from our analysis. Taken together, this work identifies key host-specific factors associated with intratumoral immune composition in gastric cancer and offers an immunological classification system that can effectively identify patients likely to benefit from immune-based therapies.

Gastric cancer (GC) is linked to high morbidity and mortality rates. Approximately two-thirds of GC patients are diagnosed at an advanced or metastatic stage. Conventional treatments for GC, including surgery, radiotherapy, and chemotherapy, offer limited prognostic improvement. Recently, immunotherapy has gained attention for its promising therapeutic effects in various tumors. Immunotherapy functions by activating and regulating the patient's immune cells to target and eliminate tumor cells, thereby reducing the tumor burden in the body. Among immunotherapies, immune checkpoint inhibitors (ICIs) are the most advanced. ICIs disrupt the inhibitory protein-small molecule (PD-L1, CTLA4, VISTA, TIM-3 and LAG3) interactions produced by immune cells, reactivating these cells to recognize and attack tumor cells. However, adverse reactions and resistance to ICIs hinder their further clinical and experimental development. Therefore, a comprehensive understanding of the advancements in ICIs for GC is crucial. This article discusses the latest developments in clinical trials of ICIs for GC and examines combination therapies involving ICIs (targeted therapy, chemotherapy, radiotherapy), alongside ongoing clinical trials. Additionally, the review investigates the tumor immune microenvironment and its role in non-responsiveness to ICIs, highlighting the function of tumor immune cells in ICI efficacy. Finally, the article explores the prospects and limitations of new immunotherapy-related technologies, such as tumor vaccines, nanotechnologies, and emerging therapeutic strategies, aiming to advance research into personalized and optimized immunotherapy for patients with locally advanced gastric cancer.

The development of Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2) inhibitors is a hot spot in the research and development of antitumor drugs, which may induce immunomodulatory effects in the tumor microenvironment and participate in anti-tumor immune responses. To date, several SHP2 inhibitors have made remarkable progress and entered clinical trials for the treatment of patients with advanced solid tumors. Multiple compounds derived from natural products have been proved to influence tumor cell proliferation, apoptosis, migration and other cellular functions, modulate cell cycle and immune cell activation by regulating the function of SHP2 and its mutants. However, there is a paucity of information about their diversity, biochemistry, and therapeutic potential of targeting SHP2 in tumors. This review will provide the structure, classification, inhibitory activities, experimental models, and antitumor effects of the natural products. Notably, this review summarizes recent advance in the efficacy and pharmacological mechanism of natural products targeting SHP2 in inhibiting the various signaling pathways that regulate different cancers and thus pave the way for further development of anticancer drugs targeting SHP2.

The modulation of the N-glycosylation status in immune checkpoints, particularly the PD-1/PD-L1 axis, has emerged as a promising approach to enhance cancer immunotherapies. While immune checkpoint inhibitors (ICIs) targeting PD-1 and PD-L1 have achieved significant clinical success, recent studies highlight the critical role of N-glycosylation in regulating their expression, stability, and function. Alterations in N-glycosylation might affect the efficacy of ICIs by modulating the interactions between immune checkpoints and antibodies used in therapy. This review focuses on the glycosylation of PD-1 and its ligands PD-L1 and PD-L2, examining how N-glycans influence immune responses and contribute to immune evasion by tumors. It explores innovative strategies to modulate glycosylation in tumor and immune cells, including the use of N-glycosylation inhibitors and novel genetic manipulation techniques. Understanding the interplay between N-glycosylation and immune checkpoint functions is essential for optimizing immunotherapy outcomes and overcoming therapeutic resistance in cancer patients.

Non-muscle invasive bladder cancer (NMIBC) represents a significant clinical challenge due to its high recurrence rate and need for frequent monitoring. The current treatment modality is bacillus Calmette-Guérin (BCG) therapy combined with chemotherapy after transurethral resection of the bladder tumor (TURBT), which is highly effective in most patients. Yet, the cancer becomes resistant to these treatments in 30-40% of patients, necessitating the need for new treatment modalities. In the cancer world, the development of immune checkpoint inhibitors that target molecules, such as programmed cell death protein-1 (PD-1), its ligand, PD-L1, and Cytotoxic T-lymphocyte-associated protein-4 (CTLA-4), have revolutionized the treatment of many cancer types. PD-1/PD-L1 and CTLA-4 are shown to be upregulated in NMIBC in certain circumstances. PD-1/PD-L1 interactions play a role in immune evasion by suppressing T cell activity within the tumor microenvironment (TME), while the binding of CTLA-4 on T cells leads to downregulation of the immune response, making these pathways potential immunotherapeutic targets in NMIBC. This review seeks to understand the role of these therapies in treating NMIBC. We explore the cellular and non-cellular immune landscape in the TME of NMIBC, including Tregs, T effector cells, macrophages, B cells, and relevant cytokines. We also discuss the biological role of PD-1/PD-L1 and CTLA-4 while covering the rationale for these immunotherapies in NMIBC. Finally, we cover key clinical trials that have studied these treatments in NMIBC clinically. Such a study will be helpful for urologists and oncologists to manage patients with NMIBC more effectively.

Immunotherapy and chemoimmunotherapy are standard treatments for non-oncogene-addicted advanced non-small cell lung cancer (NSCLC). Currently, a limited number of biomarkers, including programmed death-ligand 1 (PD-L1) expression, microsatellite instability (MSI), and tumor mutational burden (TMB), are used in clinical practice to predict benefits from immune checkpoint inhibitors (ICIs). It is therefore necessary to search for novel biomarkers that could be helpful to identify patients who respond to immunotherapy. In this context, research efforts are focusing on different cells and mechanisms involved in anti-tumor immune response. Herein, we provide un updated literature review on the role of eosinophils in cancer development and immune response, and the functions of some cytokines, including IL-31 and IL-33, in eosinophil activation. We discuss available data demonstrating a correlation between eosinophils and clinical outcomes of ICIs in lung cancer. In this context, we underscore the role of absolute eosinophil count (AEC) and tumor-associated tissue eosinophilia (TATE) as promising biomarkers able to predict the efficacy and toxicities from immunotherapy. The role of eosinophils and cytokines in NSCLC, treated with ICIs, is not yet fully understood, and further research may be crucial to determine their role as biomarkers of response. Artificial intelligence, through the analysis of big data, could be exploited in the future to elucidate the role of eosinophils and cytokines in lung cancer.

Mitochondria-related genes (MitoRGs) play a critical role in the pathogenesis of various cancer types. This study aims to develop a novel prognostic model based on a MitoRGs signature for patients with diffuse large B cell lymphoma (DLBCL).

Clinical data and gene expression profiles of DLBCL patients were obtained from four datasets in the Gene Expression Omnibus (GEO) database. The Least Absolute Shrinkage and Selection Operator (Lasso) Cox regression analysis, along with multivariate Cox regression analysis, was employed to develop a prognostic MitoRGs signature for patients with DLBCL within the training cohort. The prognostic efficacy of the model was assessed using Kaplan-Meier survival analysis and Receiver Operating Characteristic (ROC) curve analysis. The validation cohorts were used to substantiate the model's predictive capability. Single-sample gene set enrichment analysis (ssGSEA) was employed to examine immune infiltration across various risk groups, and the sensitivities to potential therapeutic agents for patients with DLBCL were also assessed. The role of the mitochondrial-related gene PCK2 in cell proliferation and apoptosis was investigated under varying glucose concentrations.

An eight-MitoRG signature exhibited independent prognostic significance and robust predictive capability for the survival outcomes of DLBCL patients. Notably, it effectively predicted prognosis across various DLBCL patient subgroups and enhanced the prognostic utility of the International Prognostic Index (IPI) score. Analyses utilizing ssGSEA and assessments of drug sensitivities identified distinct patterns of immune infiltration and differential responses to therapeutic agents among patients stratified into various risk groups. Moreover, a prognostic nomogram integrating age, IPI score, and MitoRGs signature was further developed, demonstrating enhanced prognostic accuracy and clinical applicability for DLBCL patients. In addition, research on phosphoenolpyruvate carboxykinase 2 (PCK2) indicated that silencing PCK2 expression inhibits cellular proliferation and induces apoptosis under conditions of low glucose.

We developed an innovative prognostic MitoRGs signature to predict outcomes and enhance the prognostic utility of the IPI score in DLBCL, offering a novel perspective for the treatment of DLBCL.

Background: Chronic lymphocytic leukemia (CLL) is characterized by the proliferation of dysfunctional B cells, resulting in significant immune dysregulation. Patients with CLL exhibit varied responses to B cell receptor (BCR) targeted therapies, emphasizing the need for tailored immunotherapy approaches. This study investigated B cell function in untreated patients with CLL, and we further explored the effects of ex vivo protein kinase C activation on immune checkpoint expression and B cell profiles. Methods: Peripheral blood samples were collected from 21 untreated patients with CLL at King Edward Hospital in South Africa, between 2019 and 2022. B cells were stimulated with phorbol myristate acetate (PMA) and ionomycin. Using flow cytometry, the study explored the levels of B cell subsets and immune checkpoint proteins programmed cell death 1 (PD-1), programmed cell death-ligand 1 (PD-L1), programmed cell death-ligand 2 (PD-L2) and cytotoxic T-lymphocyte associated protein 4 (CTLA-4) expression on various B cell subsets. Results: PMA and ionomycin B cell stimulation upregulated PD-1, CTLA-4 and PD-L2 expression on B cell subsets (p < 0.01). As expected, monoclonal antibodies targeting PD-1, PD-L1 and CTLA-4 significantly downregulated the CTLA-4 expression of B cell subsets (p < 0.05), while PD-L2 exhibited varied responses in different B cell subsets. Moreover, PD-1 and PD-L1 expression on total B cells significantly declined following their blockage (p < 0.01). In addition, these monoclonal antibodies increased the levels of CD19+CD27+ B cells (p < 0.0128) and activated CD19+CD27+ B cells (p < 0.01). Conclusions: Protein kinase C activation on B cells stimulates immune checkpoint expression. The use of monoclonal antibodies on B cells plays a critical role in the B cell function through the reduction in CD38 expressing activated B cells and upregulation of CD19+CD27+ B cells. Moreover, the monoclonal antibody targeting PD-1, PD-L1 and CTLA-4 are effective in reducing the expression of CTLA-4 on B cell subsets, while PD-1 and PD-L1 blockage may be effective in reducing the expression of these immune checkpoints on total B cells.

Several studies have suggested that inflammatory proteins may be associated with Coronavirus disease 2019 (COVID-19). However, the specific causal relationship between the 2 and whether blood metabolites act as mediators remains unclear. Therefore, the purpose of the present study is to investigate the causal relationship between inflammatory proteins and COVID-19 and to identify and quantify the role of blood metabolites as potential mediators. Two-sample Mendelian randomization (MR) and 2-step mediated MR analyses were used to investigate the causal relationships between 91 inflammatory proteins, 486 blood metabolites and COVID-19. A random-effects inverse variance weighted (IVW) approach was used as the primary analytical method, supplemented by weighted medians, MR-Egger and MR multivariate residual sums, and outliers to test MR hypotheses. Our results showed that 2 inflammatory proteins (interleukin-10 and interleukin-18) were positively associated with COVID-19 risk, while 1 inflammatory protein (PD-L1) was negatively associated. Further validation was performed using sensitivity analysis. The results of mediated MR showed that Betaine was a mediator of PD-L1 to COVID-19 with a mediation ratio of 15.92%. Our study suggests a genetic causality between specific inflammatory proteins and COVID-19, highlights the potential mediating role of the blood metabolite betaine, and contributes to a deeper understanding of the mechanism of action of severe COVID-19.

Immunotherapy targeting immune checkpoints has gained traction across various cancer types in clinical settings due to its notable advantages. Despite this, the overall response rates among patients remain modest, alongside issues of drug resistance and adverse effects. Hence, there is a pressing need to enhance immune checkpoint blockade (ICB) therapies. Post-translational modifications (PTMs) are crucial for protein functionality. Recent research emphasizes their pivotal role in immune checkpoint regulation, directly impacting the expression and function of these key proteins. This review delves into the influence of significant PTMs-ubiquitination, phosphorylation, and glycosylation-on immune checkpoint signaling. By targeting these modifications, novel immunotherapeutic strategies have emerged, paving the way for advancements in optimizing immune checkpoint blockade therapies in the future.

Background/Objectives: Finotonlimab (SCTI10A) is a humanized anti-PD-1 antibody tested in Phase III trials for several solid tumor types. Methods: This study characterized the in vitro and in vivo efficacy, Fc-mediated effector function, and non-clinical PK/PD properties of finotonlimab. Results: The results demonstrated that finotonlimab is effective in stimulating human T cell function in vitro and exhibits marked antitumor efficacy in vivo using both PD-1-humanized and PBMC-reconstructed mouse models. Additionally, finotonlimab exhibited minimal impact on the activation of effector cells via Fc receptor-dependent pathways, potentially facilitating PD-1+ T cell killing. In cynomolgus monkeys, finotonlimab exhibited a nonlinear pharmacokinetic (PK) profile in a dose-dependent manner, and a receptor occupancy rate of approximately 90% was observed at 168 h following a single administration of 1 mg/kg. Finotonlimab's PK profile (especially Cmax) was better than that of marketed antibodies. Following a 13-week successive administration of finotonlimab, a pharmacodynamic analysis revealed that a sustained mean receptor occupancy of PD-1 molecules on circulating T cells remained at or above 93% for up to 8 weeks, even at a dose of 3 mg/kg, and that there were higher antibody accumulations in different dose groups. Conclusions: Taken together, the preclinical findings are promising and provide the groundwork for evaluating the efficacy and pharmacodynamic characteristics of finotonlimab in clinical trials.

Uncovering early gene network changes of human hematopoietic stem cells (HSCs) leading to differentiation induction is of utmost importance for therapeutic manipulation. We employed single cell proteo-transcriptomic sequencing to FACS-enriched bone marrow hematopoietic stem and progenitor cells (HSPCs) from 15 healthy donors. Pseudotime analysis reveals four major differentiation trajectories, which remain consistent upon aging, with an early branching point into megakaryocyte-erythroid progenitors. However, young donors suggest a more productive differentiation from HSPCs to committed progenitors of all lineages. tradeSeq analysis depicts continuous changes in gene expression of HSPC-related genes (DLK1, ADGRG6), and provides a roadmap of gene expression at the earliest branching points. We identify CD273/PD-L2 to be highly expressed in a subfraction of immature multipotent HSPCs with enhanced quiescence. Functional experiments confirm the immune-modulatory function of CD273/PD-L2 on HSPCs in regulating T-cell activation and cytokine release. Here, we present a molecular map of early HSPC differentiation across human life.

Immune checkpoint inhibitor (ICI) therapies have revolutionized cancer therapy and improved patient outcomes in a range of cancers. ICIs enhance anti-tumour immunity by targeting the inhibitory checkpoint receptors CTLA-4, PD-1, PD-L1, and LAG-3. Despite their success, efficacy, and tolerance vary between patients, raising new challenges to improve these therapies. These could be addressed by the identification of robust biomarkers to predict patient outcome and a more complete understanding of how ICIs affect and are affected by the tumour microenvironment (TME). Despite being the first ICIs to be introduced, anti-CTLA-4 antibodies have underperformed compared with antibodies that target the PD-1/PDL-1 axis. This is due to the complexity regarding their precise mechanism of action, with two possible routes to efficacy identified. The first is a direct enhancement of effector T-cell responses through simple blockade of CTLA-4-'releasing the brakes', while the second requires prior elimination of regulatory T cells (TREG) to allow emergence of T-cell-mediated destruction of tumour cells. We examine evidence indicating both mechanisms exist but offer different antagonistic characteristics. Further, we investigate the potential of the soluble isoform of CTLA-4, sCTLA-4, as a confounding factor for current therapies, but also as a therapeutic for delivering antigen-specific anti-tumour immunity.

The programmed cell death 1 (PD-1) is an immune checkpoint that mediates immune evasion of tumors. Alternative splicing (AS) such as intron retention (IR) plays a crucial role in the immune-related gene processing and its function. However, it is not clear whether PDCD1 encoding PD-1 exists as an IR splicing isoform and what underlying function of such isoform plays in tumor evasion.

An AS isoform of human PDCD1, characterized by the second IR and named PD-1IR2, was identified by reverse transcription-PCR (RT-PCR) and Sanger sequencing. The expression profile of PD1IR2 was assessed by quantitative RT-PCR and flow cytometry, while its function was evaluated through immune cell proliferation, cytokine interleukin 2 secretion, and tumor cell killing assays. PDCD1IR2 CKI mice which specifically conditional knock-in PDCD1IR2 in T cells and humanized peripheral blood mononuclear cells (PBMC)-NOG (NOD.Cg-PrkdcscidIL2rgtm1Sug/JicCrl) mice were utilized to further confirm the physiological function of PD-1IR2 in vivo.

PD-1IR2 is expressed in a variety of human leukemia cell lines and tumor-infiltrating lymphocytes. PD-1IR2 expression is induced on T cell activation and regulated by the RNA-binding protein hnRNPLL. PD-1IR2 negatively regulates the immune function of CD8+ T cells, indicated by inhibiting T cell proliferation, cytokine production, and tumor cell killing in vitro. PD-1IR2+ CD8+ T cells show impaired antitumor function, which consequently promote tumor evasion in a conditional knock-in mouse model and a PBMC-engrafted humanized NOG mouse model. PD-1IR2 mice exhibit resistance to anti-PD-L1 therapy compared with wild-type mice.

PD-1IR2 is a potential immune checkpoint that may mediate potential resistance to immune checkpoint therapy.

Cancer remains a significant public health issue worldwide, standing as a primary contributor to global mortality, accounting for approximately 10 million fatalities in 2020 [...].

Cervical cancer remains a significant global health challenge, ranking as the fourth most common cancer among women. Persistent infection with high-risk human papillomavirus (HPV) is the primary etiological factor, leading to immune evasion mechanisms that promote tumor development and progression. Immunotherapy has emerged as a transformative approach in the management of cervical cancer, aiming to restore and enhance the body's immune response against tumor cells. Checkpoint inhibitors targeting programmed death-1 (PD-1) and its ligand (PD-L1) have shown promising results in patients with advanced or recurrent cervical cancer. Pembrolizumab, a PD-1 inhibitor, has been approved for PD-L1-positive cervical cancer, demonstrating durable responses. However, low response rates necessitate exploration of combination strategies. Trials are underway combining checkpoint inhibitors with chemotherapy, radiation, or other immunotherapeutic agents to enhance efficacy. Therapeutic vaccines targeting HPV antigens, such as E6 and E7 oncoproteins, are also a focus of active research. These vaccines aim to elicit robust cytotoxic T-cell responses, offering a potential strategy for early intervention and disease control. Adoptive T-cell therapies, including engineered T-cell receptor (TCR) and chimeric antigen receptor (CAR)-T cells, represent cutting-edge advancements, though challenges with tumor heterogeneity and off-target effects persist. However, challenges such as limited response rates and immune evasion mechanisms remain. The tumor microenvironment (TME) in cervical cancer, characterized by immunosuppressive cells and cytokines, poses a significant barrier to effective immunotherapy. Emerging approaches targeting the TME, such as cytokine modulation, hold promise in overcoming resistance mechanisms. Key gaps include a lack of biomarkers for patient selection, insufficient understanding of TME dynamics, and suboptimal strategies for overcoming antigen heterogeneity and immune resistance. This review addresses these issues by providing a comprehensive analysis of the current landscape of cervical cancer immunotherapy, identifying critical barriers, and highlighting emerging approaches, such as combination therapies, novel immune targets, and strategies to modulate the TME, to guide future research and clinical practice.

Despite its known role in promoting tolerance, the function of programmed cell death protein 1/programmed death ligand 1 in antibody-mediated rejection is less clear. We aimed to clarify this role by examining expression of programmed cell death protein 1/programmed death ligand 1 in renal allografts diagnosed with antibody-mediated rejection.

We examined 110 patients: 68 with pure antibody-mediated rejection (group 1) and 42 with both antibody-mediated rejection and T-cell mediated rejection (group 2). Renal immune cell infiltration, cytokine expression, and programmed cell death protein 1/programmed death ligand 1 expres-sion were examined immunohistochemically.

Expression of programmed cell death protein 1/programmed death ligand 1 in endothelial and inflammatory cells was higher in group 2 versus in group 1 (P < .001). Expression of programmed cell death protein 1/programmed death ligand 1 increased with immune cell infiltration. An inverse relationship existed between peritubular capillary DR expression and programmed cell death protein 1/programmed death ligand 1 interaction, with a positive correlation with tubular HLA-DR. Development of interstitial fibrosis was shown in 52.3% of patients with endothelial programmed cell death protein 1/programmed death ligand 1 interaction compared with 12.1% without this interaction (P < .001). Ten-year survival rate was 27.3% in patients with versus 66.7% in patients without endothelial programmed cell death protein 1/programmed death ligand 1 (P < .001) and 31.3% in patients with and 66.1% in patients without inflammatory cell programmed cell death protein 1/programmed death ligand 1 expression (P < .001).

Heightened immunological nature in antibody-mediated rejection may influence the unexpected functions of programmed death ligand 1. Inhibitory functions of the programmed cell death protein 1/programmed death ligand 1 pathway may be less effective under strong T-cell activation with high immunological costimulation in antibody-mediated rejection.

Heterobivalent fusion aptamers that target a single protein show significant promise for studying protein-protein interactions. However, a major challenge is finding two distinct aptamers that can simultaneously recognize the same protein. In this study, we used a novel technique called Aptamer-Assisted DNA SELEX (AADS) to isolate two distinct aptamers capable of recognizing different sites on the programmed death-ligand 1 (PD-L1) protein. Initially, Aptamer 1 (P1C2) was identified by using conventional DNA SELEX targeting the PD-L1 protein. Subsequently, Aptamer 2 (P1CSC) was obtained via AADS, which was designed to bind to the PD-L1/P1C2 complex. After confirming that both aptamers could simultaneously recognize the PD-L1 protein, we engineered fusion aptamers by optimizing their orientation and linker sequences, resulting in the creation of the optimized fusion aptamer, P1CSC-T7-P1C1. Our fusion aptamer targeting PD-L1 demonstrated remarkable specificity and affinity, effectively inhibiting PD-1/PD-L1 interactions at both the protein and cellular levels. These findings highlight the potential of fusion aptamers via AADS as powerful tools for targeting the PD-L1 protein and cancer cells (A549 cells). This represents a significant advancement in aptamer-based molecular recognition and has the potential to drive innovation as a versatile method for targeting a wide range of proteins.

In recent years, tumor immunotherapy has made significant breakthroughs in the treatment of malignant tumors. However, individual differences in efficacy have been observed in clinical practice. There is increasing evidence that gut microbial metabolites influence the efficacy of distal tumor immunotherapy via the gut-liver axis, the gut-brain axis and the gut-breast axis, a process that may involve modulating the expression of immune cells and cytokines in the tumor microenvironment (TME). In this review, we systematically explore the relationship between gut microbial metabolites and tumor immunotherapy, and examine the corresponding natural products and their mechanisms of action. The in-depth exploration of this research area will provide new ideas and strategies to enhance the efficacy of tumor immunotherapy and mitigate adverse effects.

Melanoma represents a significant public health challenge due to its increasing incidence and potential for metastasis. This review will explore the current clinical approaches to the management of melanoma, focusing on advancements in diagnosis, treatment, and prognosis. Methods for early detection and accurate staging have been enhanced by new diagnostic strategies. Treatment modalities have expanded beyond traditional surgical excision to include targeted therapy and immunotherapy. Prognostic assessment has benefited from the development of novel biomarkers and genetic profiling. This review will highlight the progress made in the multidisciplinary management of melanoma, underscoring the importance of continuous research to improve patient outcomes.

Achyranthes japonica (Miq.) Nakai (AJN) and Melandrium firmum (Siebold and Zucc.) Rohrb. (MFR) are medicinal plants recognized for their bioactive phytochemicals, including ecdysteroids, anthraquinones, and flavonoids. This study investigates the anticancer properties of key constituents of these plants, focusing on the BK002 formulation, a novel combination of AJN and MFR. Specifically, the research employs advanced molecular docking and in silico analyses to assess the interactions of bioactive compounds ecdysterone, inokosterone, and 20-hydroxyecdysone (20-HE) with key prostate cancer-related network proteins, including 5α-reductase, CYP17, DNMT1, Dicer, PD-1, and PD-L1. Molecular docking techniques were applied to evaluate the binding affinities contributions of the bioactive compounds in BK002 against prostate cancer-hub network targets. The primary focus was on enzymes like 5α-reductase and CYP17, which are central to androgen biosynthesis, as well as on cancer-related proteins such as DNA methyltransferase 1 (DNMT1), Dicer, programmed death-1 (PD-1), and programmed death ligand-1 (PD-L1). Based on data from prostate cancer patients, key target networks were identified, followed by in silico analysis of the primary bioactive components of BK002.In silico assessments were conducted to evaluate the safety profiles of these compounds, providing insights into their therapeutic potential. The docking studies revealed that ecdysterone, inokosterone, and 20-hydroxyecdysonec demonstrated strong binding affinities to the critical prostate cancer-related enzymes 5α-reductase and CYP17, contributing to a potential reduction in androgenic activity. These compounds also exhibited significant inhibitory interactions with DNMT1, Dicer, PD-1, and PD-L1, suggesting a capacity to interfere with key oncogenic and immune evasion pathways. Ecdysterone, inokosterone, and 20-hydroxyecdysone have demonstrated the ability to target key oncogenic pathways, and their favorable binding affinity profiles further underscore their potential as novel therapeutic agents for prostate cancer. These findings provide a strong rationale for further preclinical and clinical investigations, supporting the integration of BK002 into therapeutic regimens aimed at modulating tumor progression and immune responses.

Resistance to anti-PD-1 therapy in melanoma remains a major obstacle in achieving effective and durable treatment outcomes, highlighting the need to understand and address the underlying mechanisms. The first key factor is innate anti-PD-1 resistance signature (IPRES), an expression of a group of genes associated with tumor plasticity and immune evasion. IPRES promotes epithelial-to-mesenchymal transition (EMT), increasing melanoma cells' invasiveness and survival. Overexpressed AXL, TWIST2, and WNT5a induce phenotypic changes. The upregulation of pro-inflammatory cytokines frequently coincides with EMT-related changes, further promoting a resistant and aggressive tumor phenotype. Inflamed tumor microenvironment may also drive the expression of resistance. The complexity of immune resistance development suggests that combination therapies are necessary to overcome it. Furthermore, targeting epigenetic regulation and exploring novel approaches such as miR-146a modulation may provide new strategies to counter resistance in melanoma.

Atopic dermatitis (AD) is a chronic inflammatory skin disease with a complex relationship to allergens. While AD itself is not an allergic reaction and does not necessarily involve allergen sensitization, AD patients show higher rates of sensitization to food and inhalant allergens compared to the general population. Recent evidence refining the "dual allergen exposure hypothesis" demonstrates that early oral exposure to allergens through an intact gastrointestinal barrier typically promotes tolerance, while exposure through compromised skin or respiratory barriers often leads to sensitization. Therefore, the impaired skin barrier function in AD patients increases the risk of transcutaneous sensitization and may interfere with oral tolerance development. Interestingly, AD patients' sensitivity to contact allergens (such as metals and fragrances) is not necessarily higher than that of the general population, which may be related to the inherent properties of these allergens. Personalized allergen testing can help guide appropriate allergen avoidance and reintroduction strategies in AD management. The insights into optimal allergen exposure conditions have also expanded the potential applications of allergen-specific immunotherapy in preventing AD onset in high-risk populations and halting the atopic march.

Ovarian cancer (OC) is the most lethal gynecologic malignancy, characterized by multiple histological subtypes, each with distinct pathological and clinical features. Current treatment approaches include cytotoxic chemotherapies, poly(ADP-ribose) polymerase (PARP) inhibitors, bevacizumab, hormonal therapy, immunotherapy, and antibody-drug conjugates (ADCs). In this review we discuss immune evasion mechanisms in OC and the role of genetics, the tumor microenvironment, and tumor heterogeneity in influencing these processes. We also discuss the use of immunotherapies for OC treatment, either alone or in combination with other anticancer agents, with a focus on their clinical outcomes. Finally, we highlight emerging immunotherapies that have either succeeded or are on the verge of significantly impacting cancer treatment, and we discuss their potential utility in the effective treatment of OC.

Immune checkpoint blockade (ICB) therapies have emerged as a promising avenue for the treatment of various cancers. Despite their success, the efficacy of these treatments is variable across patients and cancer types. Numerous single-cell RNA-sequencing (scRNA-seq) studies have been conducted to unravel cell-specific responses to ICB treatment. However, these studies are limited in their sample sizes and require advanced coding skills for exploration. Here, we have compiled eight scRNA-seq datasets from nine cancer types, encompassing 223 patients, 90,270 cancer cells, and 265,671 other cell types. This compilation forms a unique resource tailored to investigate how cancer cells respond to ICB treatment across cancer types. We meticulously curated, quality-checked, pre-processed, and analyzed the data, ensuring easy access for researchers. Moreover, we designed a user-friendly interface for seamless exploration. By sharing the code and data for creating these interfaces, we aim to assist fellow researchers. These resources offer valuable support to those interested in leveraging and exploring single-cell datasets across diverse cancer types, facilitating a comprehensive understanding of ICB responses.

Transplant recipients face increased cancer mortality due to immunosuppressive treatments. Immune checkpoint inhibitors (ICI) have improved survival rates, but data on the use of these agents in transplant recipients is scarce. ICI may trigger allograft rejection, but the absolute risk of AR between the different ICI classes remains to be defined.

VigiBase® (WHO's pharmacovigilance database) was queried for reports of AR involving CTLA4, PD1, or PDL1 inhibitors. Disproportionality analysis compares the proportion of reports with a specific adverse drug reaction (ADR) and a given drug to the proportion of reports with the same ADR and other drugs. A lower 95% confidence interval for the Information Component (IC) >0 suggests a signal. The comparative Reporting Odds Ratios (ROR) for AR, between PD1 and PDL1 inhibitors, was calculated.

We gathered 159 AR involving an ICI, especially nivolumab (73, 45.9%), mostly affecting kidneys (87, 54.7%). Median time to onset: 28 days. Fatal outcome: 36 reports (22.6%). ICI were significantly associated with AR: IC=1.7 [1.4;1.9]. Specifically, PD1 inhibitors yielded an IC of 2.0 [1.7;2.2] (152 reports observed compared to 38 expected). By contrast, the IC of PDL1 inhibitors was negative: -2.6 [-6.4;-1.0] (1 observed, 9 expected). The comparative ROR of PD1 compared to PDL1 inhibitors was 33.7 [4.7;240.9] (p=0.0005).

We confirm the association between ICI treatment and AR. Notably, PDL1 inhibitors showed surprisingly low AR reports compared to CTLA4 and PD1 inhibitors. Further prospective studies are warranted to confirm whether PDL1 inhibitors indeed reduce AR risk compared to other ICI.