Search Results (805)

Background/Objectives: Whilst adoptive cell therapy (ACT) using chimeric antigen receptor-engineered T (CAR-T) cells represents an efficient approach for the treatment of patients suffering from several hematological malignancies, solid tumors have been shown to be far more challenging to tackle, mainly due to the hostile tumor microenvironment that inhibits optimal T cell functionality. As proven by the broad clinical success of immune checkpoint inhibitors, blocking the interaction of programmed cell death ligand 1 (PD-L1) expressed on tumor cells and the checkpoint receptor programmed cell death 1 (PD-1) expressed on activated T cells allows an intrinsic T cell-mediated anti-tumor response to be unleashed. We developed a cellular product (MDG1015) consisting of New York esophageal squamous cell carcinoma-1 (NY-ESO-1)/L antigen family member 1a (LAGE-1a)-specific CD8+ T cell receptor-transduced (TCR-)T cells co-expressing the costimulatory switch protein (CSP) PD1-41BB, which turns an inhibitory signal mediated by the PD-1:PD-L1 axis into positive T cell costimulation. Methods: In vitro co-cultures of MDG1015 and PD-L1-positive or -negative target cells were used to analyze TCR-T cell functionality, such as TCR-T (poly-)cytokine release, the killing of target cells, and TCR-T proliferation. The safety of MDG1015 was evaluated via different panels of antigen-negative cell lines or primary cells expressing or lacking PD-L1. Results: Preclinical analyses demonstrated TCR-gated activation of the CSP, leading to enhanced functionality of MDG1015 against antigen-expressing, PD-L1-positive tumor cells without any impact on antigen-negative target cells. Conclusions: The favorable, preclinical functionality and safety profile qualifies MDG1015 as a promising cellular therapy for explorative clinical testing in hard-to-treat solid tumor indications. Full article

Background/Objectives: Programmed cell death-ligand 1 (PD-L1) is one of the key biomarkers for immune checkpoint inhibitors. We are developing a novel PD-L1 CAL10 immunohistochemistry (IHC) assay (Leica Biosystems) on BOND-III staining system and have analyzed its initial performance by comparing it to the PD-L1 SP263 assay (Ventana) assay in a feasibility study. The study objective was to determine the concordance of the Leica Biosystems PD-L1 CAL10 assay with the comparator SP263 assay at the tumor proportion score (TPS) cutoff of ≥50% in non-small cell lung cancer (NSCLC) tissue samples. Additionally, the concordance between the two assays at the TPS cutoff of ≥1% was also evaluated. For informational purposes, we also evaluated the concordance between manual slide reads vs. digital reads (whole slide images generated using the Aperio GT 450) for the CAL10 assay. Methods: Two pathologists read and scored the glass slides. The CAL10 PD-L1 assay concordance with the PD-L1 SP263 assay was evaluated by assessing the agreement rates between the two assays. Results: The lower bound of the 95% confidence interval (CI) of the overall percent agreement (OPA) at ≥50% cutoff was 86.2%, while for ≥1% TPS cutoff, it was 94.0%, which met the predefined target of a minimum OPA lower bound of the 95% CI value of 85%. Conclusions: The Leica Biosystems CAL10 PD-L1 assay has demonstrated comparable performance to the SP263 assay. Additionally, the PD-L1 CAL10 stained glass slides and the corresponding whole side images generated by GT 450 showed comparable concordance rate. Full article

Background/Objectives: Diffuse large B cell lymphoma (DLBCL) is a highly heterogeneous and aggressive lymphoma with a high incidence rate. Although modern therapeutic approaches have significantly improved patient survival rates, treatment relapse and drug resistance remain major clinical challenges. Programmed cell death (PCD) promotes tumorigenesis and regulates the tumor microenvironment (TME) and drug sensitivity. Exploring the application potential of PCD in DLBCL could pave the way for new treatment strategies for this malignancy. Methods: We systematically analyzed 13 types of PCD pathways and integrated transcriptomic and clinical data from 832 DLBCL patients (GSE10846, GSE11318, and GSE87371). A PCD-based prognostic signature, termed the Programmed Cell Death Score (PCDS), was constructed using 20 key PCD-related genes. Its clinical relevance was evaluated through survival analysis, drug response profiling, and tumor immune infiltration assessment using CIBERSORT, ESTIMATE, and ssGSEA algorithms. Results: The PCDS robustly stratified patients by survival and outperformed conventional clinical indicators such as age, stage, Eastern Cooperative Oncology Group (ECOG), and lactate dehydrogenase (LDH) in prognostic prediction. High-PCDS tumors were associated with immune suppression, characterized by reduced CD8⁺ T cell infiltration, elevated M2 macrophages, and increased programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) expression. Drug sensitivity analysis revealed that high-PCDS patients may benefit more from agents like sorafenib and fulvestrant, while low-PCDS patients responded better to NU7441. Functional validation using DLBCL cell lines and xenografts confirmed the oncogenic role of a representative gene (CTH) within the model. Conclusions: This study presents a novel prognostic scoring system derived from multiple PCD pathways that effectively stratifies DLBCL patients by risk and therapeutic responsiveness. Notably, the PCDS is closely associated with key immunological characteristics of the TME. These findings advance personalized treatment strategies and support clinically relevant decision-making in DLBCL. Full article

The immune landscape plays an important role in various pituitary diseases, ranging from hypophysitis to pituitary neuroendocrine tumors. Moreover, the use of immune checkpoint inhibitors (ICIs) has dramatically altered the landscape of cancer treatment by improving prognosis and overall survival in a multitude of advanced-staged malignancies, though their use in pituitary neuroendocrine tumors has remained limited. In this review, we will focus on selected topics to highlight the impact of the immune microenvironment on the function of the pituitary gland, namely, animal models of autoimmune hypophysitis, including ICI-induced hypophysitis as a common adverse event, and the importance of its early recognition in patients treated with ICIs. Using a case, we will provide an overview on the epidemiology, pathogenesis, clinical spectrum, diagnosis, predictors, and management of ICI-induced hypophysitis. We will also summarize the role of the immune microenvironment in pituitary neuroendocrine tumors with programmed cell death ligand 1 as a biomarker for treatment. Lastly, we will review the role of ICIs in the management of 40 patients with aggressive and metastatic pituitary neuroendocrine tumors. Current knowledge gaps in these topics will also be highlighted. Full article

This systematic review critically evaluates the efficacy and safety of monoclonal (mAb) and polyclonal (pAb) antibody therapies in adult sepsis and septic shock by synthesizing data from 29 randomized controlled trials (RCTs) encompassing over 10,000 patients. Sepsis and septic shock continue to be major critical-care mortality causes worldwide because of simultaneous hyperinflammatory and immunosuppressive responses. The clinical results from using targeted antibody therapies to manage this dysregulated response have shown inconsistent results. We conducted a comprehensive search of MEDLINE, Embase, Cochrane CENTRAL, Web of Science, and Google Scholar (through February 2025) to identify RCTs that compared mAb and pAb treatments to placebo or standard care in adult patients with sepsis or septic shock. Monoclonal antibodies against single cytokines e.g., Tumor Necrosis Factor-alpha (TNF-α) and endotoxin, did not significantly reduce 28-day mortality in unselected cohorts, though subgroup analyses of patients with elevated Interleukin-6 (IL-6) or early septic shock showed trends toward benefit. Intravenous Immunoglobulin (IVIG) enriched for Immunoglobulin M (IgM) demonstrated the most consistent mortality reduction when administered early in hyperinflammatory phases. Emerging precision strategies—including checkpoint inhibitors targeting Programmed Cell Death Protein 1/Programmed Death-Ligand 1 inhibitors (anti–PD-1/PD-L1), complement component 5a inhibitors (anti–C5a), and anti–adrenomedullin—were safe and improved organ-support-free days and Sequential Organ Failure Assessment (SOFA) scores. According to the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach, evidence showed moderate confidence for mortality, high certainty for safety and low to moderate certainty for secondary outcomes. The use of broad single-target monoclonal treatments has failed to deliver significant improvements in sepsis patient outcomes. The most promising approaches for sepsis treatment involve biomarker-guided precision strategies and polyclonal IgM-enriched IVIG. Future sepsis trials need to implement rapid immune profiling and adaptive designs and combination regimens to achieve optimal efficacy and establish personalized guideline-based sepsis management. Full article

Background/Objectives: Fibromyalgia causes chronic long-term pain, with symptoms lasting for months to years. Given the lack of evidence-based methods for diagnosing and assessing fibromyalgia, it ranks among the most difficult chronic pain conditions to treat. Programmed cell death ligand 1 (PD-L1) can inhibit acute and chronic pain transmission by inhibiting neuronal ion channels. Methods: Here, we aimed to explore the analgesic efficacy and mechanism of PD-L1/PD1 in an intermittent cold stress-induced fibromyalgia pain mouse model. Results: Von Frey and Hargreaves tests were performed, showing that the mouse model exhibited mechanical (day 4: 2.08 ± 0.13 g, n = 9) and thermal hyperalgesia (day 4: 3.93 ± 0.45 s, n = 9). Electroacupuncture (EA) or intraventricular PD-L1 injection effectively alleviated the nociceptive response and led to low PD-1 levels in the mouse dorsal root ganglia, spinal cord, thalamus, somatosensory cortex, and cerebellum, as measured through Western blots. In contrast, the pain-related kinase levels increased after fibromyalgia induction; these effects were reversed by EA and PD-L1 via the inhibition of microglia/astrocytes and Toll-like receptor 4. Conclusions: Our results show that EA can treat fibromyalgia pain in mice through effects on the PD-L1/PD1 pathway, indicating its potential as a therapeutic target in fibromyalgia. Full article

Background: Malignant melanoma remains an oncological challenge, with advanced-stage five-year survival rates under 20%. Precise molecular imaging has become indispensable for accurate staging, selection of targeted or immunotherapies, treatment response assessment, and early detection of immune-related adverse events. This review examines the roles of PET/CT, PET/MRI, and SPECT/CT radiopharmaceuticals in melanoma management and highlights novel tracers and theranostic strategies poised to enhance precision nuclear medicine in this disease. Methods: We performed a review of English-language literature from January 2000 through June 2025, querying PubMed, Scopus, and clinical-trial registries for original research articles, meta-analyses, clinical guidelines, and illustrative case reports. Eligible studies investigated PET/CT, PET/MRI, or SPECT/CT applications in melanoma diagnosis, nodal and distant staging, therapy monitoring, irAE (immune-related adverse events) detection, and the development of emerging radiotracers or theranostic radiopharmaceutical pairs. Results:¹⁸F-FDG PET/CT demonstrated a high detection rate for distant metastases, outperforming conventional CT and MRI in advanced disease, despite limited resolution for infracentimetric nodal deposits. PET/MRI offers comparable diagnostic accuracy with superior soft-tissue contrast and improved brain lesion detection, while SPECT/CT enhanced sentinel lymph node localization prior to surgical biopsy. Also, FDG PET/CT identified visceral irAEs with great sensitivities, revealing asymptomatic toxicities in up to one-third of patients. Emerging radiotracers targeting melanin, fibroblast activation protein, PD-1 (programmed cell death protein 1)/PD-L1 (programmed cell death-ligand 1), and CD8⁺ T cells have demonstrated enhanced tumor specificity and are on their way to forming novel theranostic pairs. Conclusions: While ¹⁸F-FDG PET/CT remains the cornerstone of melanoma imaging, complementary advantages of PET/MRI and SPECT/CT imaging refine melanoma management. The advent of highly specific radiotracers and integrated theranostic approaches heralds a new era of tailored nuclear-medicine strategies, promising improved patient stratification, therapy guidance, and clinical outcomes in melanoma. Full article

Background: Various studies have demonstrated fucoidan’s immunomodulatory effects. A previous study reported the anticancer effects of Durvillaea antarctica fucoidan (DAF) via immune activation in mice. Methods: In this study, we confirmed the DAF’s pulmonary immune activation ability by nasal administration of the dendritic cells (DCs) and T cells. Furthermore, we examined its ability to enhance the efficacy of lung cancer treatment by combining it with anti-PD-L1 antibodies to activate the lung immune response. Results: Nasal DAF administration increased C-C chemokine receptor type 7 expression in DCs and promoted DC migration to the mediastinal lymph nodes (mLN). Specifically, DAF increased conventional DC type 1 (cDC1) and cDC2 numbers in mLN and potently activated cDC1. Furthermore, the nasal administration of DAF increased the production of inflammatory cytokines in the lungs and peripheral blood. Repeated intranasal administration of DAF induced T-cell activation, resulting in the enhanced production of interferon-gamma and tumor necrosis factor-alpha in CD4 T and CD8 T cells. CD8 T cells also showed increased secretion of cytotoxic mediators after DAF treatment, and the proportion of Tregs expressing FoxP3 decreased in the mLN. DAF inhibited lung cancer growth in Lewis lung carcinoma 2 cells, which was enhanced by combining it with an anti-programmed death-ligand 1 antibody. Finally, the anticancer effects of DAF were not observed in mice with depleted CD4-positive and CD8-positive cells. Conclusions: Nasal administration of DAF may inhibit lung cancer growth by inducing lung immune activation and is expected to be helpful as an immune activator for nasal administration. Full article

The field of oncology has been extensively studied to design more effective and efficient treatments. This review explores the advanced techniques that are transforming our comprehension of cancer and its constituents. Specifically, it highlights the signaling pathways that drive tumor progression, angiogenesis, and resistance to therapy, as well as the modern approaches used to identify and characterize these pathways within the tumor microenvironment (TME). Key pathways discussed in this review include vascular endothelial growth factor (VEGF), programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), and various extracellular matrix (ECM) pathways. Conventional methods of diagnosis have yielded sufficient knowledge but have failed to reveal the heterogeneity that exists within the TME, resulting in gaps in our understanding of the cellular interaction and spatial dynamics. Single-cell sequencing (SCS) and spatial transcriptomics (ST) are effective tools that can enable the dissection of the TME with the resolution capacity of a single cell. SCS allows the capture of the unique genetic and transcriptomic profiles of individual cells along with rare cell types and new therapeutic targets. ST complements this by providing a spatial map of gene expression, showing the gene expression profiles within the tumor tissue at specific sites with good accuracy. By mapping gene expression patterns at a single cell level and correlating them with the spatial locations, researchers can uncover the intricate networks and microenvironmental influences that contribute to tumor heterogeneity. Full article

Malignant neoplasms, like non-small cell lung cancer (NSCLC), remain a major global health challenge. Lung cancer is the leading cause of cancer-related deaths worldwide, with over two million new cases and 1.8 million deaths annually. NSCLC accounts for approximately 85% of cases, underscoring its substantial public health impact. Advances in molecular biology have driven the development of new therapies beyond traditional treatments. Among them, mRNA-based immunoadjuvant therapies, like cancer vaccines, have emerged as promising utilities in NSCLC by triggering targeted immune responses. The aim of this paper is to review ongoing and completed studies on mRNA vaccines in NSCLC. The efficacy of mRNA vaccines in NSCLC relies on the identification of immunogenic tumor-specific antigens, frequently derived from genomic profiling databases. Completed clinical trials have assessed the safety and potential benefit of selected mRNA vaccines—such as CV9202—administered alone or in combination with radiotherapy or tyrosine kinase inhibitors. Ongoing studies are exploring the therapeutic potential of mRNA-based approaches targeting defined molecular alterations in NSCLC, particularly in conjunction with Programmed Death-Ligand 1 (PD-L1) immune checkpoint inhibitors to enhance antitumor immune responses. mRNA vaccines have emerged as a promising therapeutic option for NSCLC, with the potential to enhance immune responses and limit tumor progression, as demonstrated in ongoing clinical trials. They offer the possibility of personalized treatment with relatively few side effects. However, larger and long-term studies are required to fully confirm their safety and efficacy. Future research should aim to identify the most effective antigens, enhance stability, and refine delivery strategies to improve efficacy and personalization, while also addressing immune suppression within the tumor microenvironment. Full article

Gastric cancer remains a major global health burden, with limited response rates to current immunotherapies targeting the programmed death-ligand 1 (PD-1/PD-L1) axis. Recent studies have identified sialic acid-binding immunoglobulin-like lectin 15 (SIGLEC-15) as a novel immune checkpoint molecule that may drive immune evasion through PD-L1–independent pathways. This study aimed to evaluate the expression patterns of SIGLEC-15 and PD-L1 in gastric adenocarcinoma and to investigate their associations with clinicopathological features and patient outcomes. We retrospectively analyzed 133 consecutive cases of gastric adenocarcinoma with complete clinicopathologic and follow-up data. Immunohistochemical staining was performed on formalin-fixed tumor samples; SIGLEC-15 expression on tumor cells was quantified by H-score (high expression defined as ≥110) and PD-L1 status by combined positive score (CPS, positive if ≥1). High SIGLEC-15 expression correlated with multiple adverse pathological features, including lymphatic (p = 0.003), venous (p = 0.030), and perineural invasion (p = 0.010), and was associated with significantly poorer 3-year overall survival (hazard ratio = 3.36, p < 0.001). While SIGLEC-15 and PD-L1 expression were not mutually exclusive, an inverse relationship was generally observed. Patients with dual positivity (SIGLEC-15 high/PD-L1 CPS ≥ 1) showed the lowest 36-month survival (32%), compared to 56% in the dual-negative group (SIGLEC-15 low/PD-L1 CPS < 1). These results highlight the clinical relevance of SIGLEC-15 as an independent marker of tumor aggressiveness and poor prognosis in gastric adenocarcinoma. Moreover, stratification based on combined SIGLEC-15 and PD-L1 CPS expression revealed that patients co-expressing high levels of both markers experienced the poorest survival outcomes. These findings suggest that the dual assessment of SIGLEC-15 and PD-L1 may enhance prognostic accuracy and support immunotherapeutic decision-making in gastric cancer. Full article

Background: Single-agent pembrolizumab represents a standard of care in the first-line treatment of patients with metastatic non-small cell lung cancer (mNSCLC) with a programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) of ≥50%. Real-world evidence is of increasing importance in oncology, as clinical trial inclusion criteria may not be truly reflective of the patient population seen in daily clinical practice. Methods: We performed a prospective–retrospective single-center study including 121 patients who received pembrolizumab as a first-line therapy for mNSCLC with a PD-L1 TPS ≥ 50%. Our aims were to make a comparison with published clinical trial results by assessing the efficacy and safety of pembrolizumab monotherapy in our population. We collected patient demographics, clinical characteristics of the disease, and treatment outcomes, including efficacy and safety. Results: A total of 121 patients were included, with a median follow-up of 40.77 months. The median progression-free survival in the real world (rwPFS) was 20.73 months (95% CI 12.24–29.22), and the median overall survival (OS) was 29.30 months (95% CI 16.57–42.04). Immune-mediated adverse events (irAEs) occurred in 42% of patients, with serious events (grade 3 or more) occurring in 12%. ECOG PS 2, male gender, squamous histology, pleural and visceral metastases, and treatment with corticosteroids prior to initiation of pembrolizumab were found to be negative predictors for overall survival, while the occurrence of irAEs was the predictor of longer survival. Conclusions: This study provides further real-world insights into the efficacy of pembrolizumab in a heterogeneous patient population with advanced NSCLC in a single center in Serbia. It also confirmed the value of good ECOS PS and the occurrence of irAEs as predictors of favorable outcomes. Full article

Background: Lung cancer has the highest lethality rate among malignancies worldwide. Immunotherapy is one of the common treatments for lung cancer patients. There are two main types of immunotherapies: one targets programmed cell death 1 (PD-1), and the other targets programmed cell death ligand 1 (PD-L1). These two belong to the class of immune checkpoint inhibitors (ICIs). However, immune-related adverse reactions (irAEs) were the main reasons affecting its clinical therapeutic effect. Methods: This retrospective cohort study analyzed red blood cell count (RBC), hematocrit (HCT), erythrocyte mean corpuscular volume (MCV) and immunotherapy outcomes in 920 lung cancer patients receiving immunotherapy from April 2019 to May 2023. Results: We found that high levels of RBC (>4.105 × 10⁹, p = 0.007, OR = 0.467, 95%CI: 0.268~0.812) and MCV (>86.35, p = 0.017, OR = 0.0.441, 95%CI: 0.224~0.865) were significantly related to the better response of ICIs immunotherapy in patients. Patients with high levels of HCT (>39.75%, p = 0.035, OR = 0.737, 95%CI: 0.555~0.979) may have a lower rate of irAEs occurrence. Meanwhile, patients with a low level of RBCs (≤4.635 × 10⁹, p < 0.001, OR = 1.636, 95%CI: 1.365~1.960) may have a longer period of PFS (progression-free survival), and patients with RBC (≤4.43 × 10⁹, p = 0.033, OR = 0.480, 95%CI: 0.244~0.941) may have a longer time of OS (overall survival). Conclusions: The findings indicate that the levels of RBC, MCV and HCT were significantly associated with the response and irAEs of ICIs in lung cancer patients. The levels of RBC might act as a possible biomarker for predicting the survival of lung cancer patients who are receiving ICI therapy. Full article

Breast cancer remains a formidable global health challenge, with triple-negative breast cancer (TNBC) posing unique clinical complexities. Characterized by its aggressive nature and limited number of specific therapeutic targets, this breast cancer subtype disproportionately affects African American women, highlighting critical disparities in care. The tumor immune microenvironment (TIME) plays a critical role in breast cancer development and response to immunotherapy, and it is essential in fostering an immunosuppressive and pro-inflammatory niche. Inflammation, primarily mediated by the NF-κB signaling pathway and chemokine signaling, particularly involving CCL2, plays a pivotal role in TNBC progression and therapy resistance. This review describes some of the molecular mechanisms of polyphenols, which are naturally occurring compounds abundant in various dietary sources, and their potential use as therapeutic agents in the management of TNBC. Polyphenolic compounds have been described as modulating the TIME through the inhibition of tumor progression, immune evasion, and therapy resistance, due to their diverse bioactivities, including anti-inflammatory, antioxidant, and anticancer properties, making them attractive candidates for combating the aggressiveness of TNBC and addressing treatment disparities. Polyphenols, such as curcumin, gossypol, butein, epigallocatechin gallate, cardamonin, and resveratrol, have demonstrated efficacy in modulating several signaling pathways within the TIME, which are implicated in the progression of TNBC. This review highlights the potential effects of polyphenols on inflammatory cytokine release, programmed cell death ligand 1 (PD-L1) expression, which is associated with immune evasion by the host cell, and various intracellular signaling cascades, demonstrating their potential use in personalized therapeutic interventions for TNBC. This study also describes differential responses of TNBC cell lines to polyphenol treatment, highlighting the importance of considering genetic variability in therapeutic strategies, as well as the importance of the interaction of polyphenols with the gut microbiome, which may establish the bioavailability and effectiveness of these compounds toward therapeutic outcomes. Further preclinical and clinical studies are warranted to fully elucidate the therapeutic potential of polyphenols and translate these findings into clinical practice, thereby improving outcomes for patients with TNBC worldwide. Full article

Bovine leukemia virus (BLV) infects B cells in ruminants and causes lymphoma after an extended latency period. Previous studies have demonstrated T-cell exhaustion through the upregulation of immunoinhibitory molecules, including programmed death-ligand 1 (PD-L1) and T-cell immunoglobulin and mucin domain-3 (TIM-3), in BLV-infected cattle. However, studying T-cell exhaustion across all BLV infection stages remains challenging due to the virus’s prolonged latency in cattle. Sheep provide a valuable model, as they develop lymphoma more rapidly than cattle. This study examined PD-L1 and TIM-3 expression kinetics and T-cell function in BLV-infected sheep. During persistent infection, PD-L1 expression was correlated with BLV proviral load. TIM-3 expression increased in CD4⁺, CD8⁺, and γδTCR⁺ T cells. Functional analysis revealed that TIM-3 blockade enhanced T-cell activation markers (CD25 and CD69) in cultured PBMCs from infected sheep and increased CD69⁺IFN-γ⁺ and CD69⁺TNF-α⁺ populations, particularly among CD4⁺ T cells. Combined PD-L1 and TIM-3 blockade significantly enhanced cytokine production in both CD4⁺ and CD8⁺ T cells, while PD-L1 blockade alone showed limited effects. These findings demonstrate the effect of TIM-3 blockade in restoring immune function during chronic BLV infection, effective both alone and in combination. This study validates sheep as a valuable model for investigating immune checkpoint dynamics and evaluating immunotherapies for BLV infection and other chronic diseases. Full article