Search Results (318)

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by high immunogenicity and specific immune signatures. Although these molecular features including elevated tumor-infiltrating lymphocytes (TILs) and programmed death-ligand 1 (PD-L1) expression provide a strong rationale for immunotherapy, clinical response remains limited due to multiple mechanisms of immune escape. This review summarizes current and emerging immunotherapeutic strategies in TNBC, including immune checkpoint inhibitors (PDL-1 and cytotoxic T-lymphocyte-associated protein 4 (CTL-4) blockade), adoptive cell therapy (ACT) (chimeric antigen receptor T-cell therapy (CAR-T) and TIL therapy), oncolytic virotherapy, and antibody-based approaches. We also discuss the mechanisms of resistance including DNA damage response alterations, anti-apoptotic signaling, and tumor microenvironment-mediated resistance. Finally, we highlight rational combination strategies, immunotherapy with chemotherapy, targeted therapy, or additional immunotherapies that aim to enhance response to immunotherapy. Ongoing advances in immunotherapy hold significant potential to improve outcomes for patients with TNBC. Full article

Norovirus is associated with vomiting and diarrhea and, in severe cases, can result in death. Currently, there is no effective treatment or vaccine for this virus. Bilateral interactions have been reported between gut microbiota and viral infection. Our laboratory has been studying the Surface layer protein A (SlpA) of a human isolate of Lactobacillus acidophilus. Previously, we reported that SlpA induces a variety of antiviral genes in human dendritic cells, suggesting it may prevent viral replication. SlpA binds to its cognate receptor SIGNR3-expressed on limited dendritic cells. To achieve a homogenous expression of the gene, we modified murine macrophage RAW 264.7 (RAW) cells by transducing SIGNR3-expressing lentivirus, resulting in RAWS cells. These cells and wild-type RAW cells were pretreated with SlpA for one hour and infected with 1 MOI of murine norovirus (MNV). We report that RAWS cells, when treated with SlpA, enhance the antiviral program to prevent viral replication, as determined by quantitative real-time PCR and viral titer. RNA isolated from MNV-infected cells revealed an elevation in two critical antiviral genes, Iigp1 and Ifit1, in SlpA-treated RAWS cells, potentially preventing viral replication. Full article

Background: Advances in molecular pathology have transformed NSCLC (Non-Small Cell Lung Cancer) diagnosis, prognosis, and treatment by enabling precise tumor characterization and targeted therapeutic strategies. We review key genomic alterations in NSCLC, including EGFR (epidermal growth factor receptor) mutations, ALK (anaplastic lymphoma kinase) and ROS1 (ROS proto-oncogene 1) rearrangements, BRAF (B-Raf proto-oncogene serine/threonine kinase) mutations, MET (mesenchymal–epithelial transition factor) alterations, KRAS (Kirsten rat sarcoma) mutations, HER2 (human epidermal growth factor receptor 2) alterations and emerging NTRK (neurotrophic receptor tyrosine kinase) fusions and AXL-related pathways. Methods: A total of 48 patients with NSCLC was analyzed, including 22 women and 26 men (mean age 70 years, range 44–86). Tumor specimens were classified histologically as adenocarcinomas (n = 81%) or squamous cell carcinomas (n = 19%). Smoking history, PD-L1 (programmed death-ligand 1) expression, and genetic alterations were assessed. NGS (Next-generation sequencing) identified genomic variants, which were classified according to ACMG (American College of Medical Genetics and Genomics) guidelines. Results: The cohort consisted of 29 former smokers, 13 current smokers, and 5 non-smokers (12%), with a mean smoking burden of 33 pack years. PD-L1 TPS (tumor proportion score) was ≥50% in 10 patients, ≥1–<50% in 22, and <1% in 15 patients. In total, 120 genomic variants were detected (allele frequency ≥ 5%). Of these, 52 (43%) were classified as likely pathogenic or pathogenic, 48 (40%) as variants of unknown significance, and 20 (17%) as benign or likely benign. The most frequently altered genes were TP53 (tumor protein p53) (31%), KRAS and EGFR (15% each), and STK11 (serine/threonine kinase 11) (12%). Adenocarcinomas accounted for 89% of all alterations, with TP53 (21%) and KRAS (15%) being most common, while squamous cell carcinomas predominantly harbored TP53 (38%) and MET (15%) mutations. In patients with PD-L1 TPS ≥ 50%, KRAS mutations were enriched (50%), particularly KRAS G12C and G12D, with frequent co-occurrence of TP53 mutations (20%). No pathogenic EGFR mutations were detected in this subgroup. Conclusions: Comprehensive genomic profiling in NSCLC revealed a high prevalence of clinically relevant mutations, with TP53, KRAS and EGFR as the dominant drivers. The strong association of KRAS mutations with high PD-L1 expression, irrespective of smoking history, highlights the interplay between genetic and immunological pathways in NSCLC. These findings support the routine implementation of broad molecular testing to guide precision oncology approaches in both adenocarcinoma and squamous cell carcinoma patients. Full article

Cell surface immune checkpoint receptors are objects for therapeutic intervention to stimulate immune cell attack of cancers. Interference between the checking ectodomain (ECD) and the natural ligand lowers constitutive restraints exerted on immune cells. This approach assumes that immune cells can do more, that a checkpoint blocker will make immune cells more effective at killing cancer cells, and that checkpoint molecules might have limited physiological roles. These assumptions may be warranted, as in the case of checkpoint-blockers towards the programmed death-ligand 1 (PD-L1) ECD, where clinical outcomes are consistently good. However, this does not appear to be the case for the universally expressed CD47 ECD. Much effort has been directed at engineering molecules that bind to the CD47 ECD to increase T cell and macrophage killing of cancers. But a wealth of clinical data do not indicate strong signals, improved killing, or meaningful survival advantages. This suggests that the CD47 ECD is a subpar target for cancer therapy. Consideration of reasons accounting for the modest benefits realized by molecules that bind to the CD47 ECD in cancer, also known as Plan A, is provided. This is followed by thoughts on what might be done, known as plan B, to identify advantages within the CD47 ECD for modulating tolerance in autoimmune diseases. Full article

Chronic lymphocytic leukemia (CLL) is a heterogenous disease, with varied clinical outcomes. Multiplex assays used to measure soluble immune checkpoints offer a less laborious method of monitoring patients with CLL, but none of these panels have been validated. The aim of the study was to assess soluble immune checkpoint profiles in patients with CLL and to correlate these with independent prognostic markers such as β2-microglobulin (B2M), Rai stage, fluorescence in situ hybridization (FISH) status, and the International Prognostic Index for Chronic Lymphocytic Leukemia (CLL-IPI). We measured plasma levels of soluble interleukin-2 receptor alpha (sCD25), T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), galectin-9, programmed cell death 1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte associated protein 4 (CTLA-4) using cytometric bead array-based assays. We further measured plasma levels of B2M using an enzyme-linked immunosorbent assay (ELISA) kit. Soluble immune checkpoints were correlated with prognostic markers. The plasma levels of sCD25, TIM-3, galectin-9, PD-1, and PD-L1 were significantly increased in patients with CLL compared to the control group, p < 0.0001. Galectin-9 plasma levels were directly associated with B2M levels (β = 0.65, p = 0.012). Our findings suggest that galectin-9 may provide valuable prognostic significance for patients with CLL. Full article

Cancer therapy resistance emerges from highly integrated molecular systems that enable tumor cells to evade cell death and survive cytotoxic therapeutic stress. High Mobility Group Box 1 (HMGB1) is increasingly gaining recognition as a central coordinator of these resistance programs. This review delineates how HMGB1 functions as a molecular switch that dynamically redistributes between cellular compartments in response to stress, with each localization enabling a distinct layer of resistance. In the nucleus, HMGB1 enhances chromatin accessibility and facilitates the recruitment of DNA repair machinery, strengthening resistance to radio- and chemotherapeutic damage. Cytosolic HMGB1 drives pro-survival autophagy, maintains redox stability, and modulates multiple regulated cell death pathways, including apoptosis, ferroptosis, and necroptosis, thereby predominantly shifting cell-fate decisions toward survival under therapeutic pressure. Once released into the extracellular space, HMGB1 acts as a damage-associated molecular pattern (DAMP) that activates key pro-survival and inflammatory signaling pathways, establishing microenvironmental circuits that reinforce malignant progression and therapy escape. HMGB1 further intensifies resistance through upregulation of multidrug resistance transporters, amplifying drug efflux. Together, these compartmentalized functions position HMGB1 as a central node in the networks of cancer therapy resistance. Emerging HMGB1-targeted agents, ranging from peptides and small molecules to receptor antagonists and nanoformulations, show promise in reversing resistance, but clinical translation will require precise, context- and redox-informed HMGB1 targeting to overcome multifactorial resistance program in refractory cancers. Full article

The tumor microenvironment (TME) orchestrates tumor growth, immune evasion, and therapeutic response in head and neck squamous cell carcinoma (HNSCC). Current immune checkpoint inhibitors (ICIs) target the programmed death receptor-1/programmed death-ligand 1 (PD-1/PD-L1) axis and improve survival in recurrent, metastatic, and locally advanced HNSCC. Tumor cells produced exosomes directly suppress cytotoxic T-lymphocytes activity by modulating immune checkpoint pathways and disrupting T-cell receptor signaling. Cancer-associated fibroblast-derived exosomes (CAF-Exos) function indirectly by conditioning immune escape and tumor growth. Together, these exosomal populations cooperate to create an immunosuppressive niche that hinders the efficacy of immunotherapies. CAF-Exos induce TME changes that exclude CD8⁺ T-cells, promote regulatory T-cells (Tregs), and upregulate PD-L1 expression in tumor cells. The bidirectional transfer of microRNAs (miRNAs) between tumor cells and CAFs enhances epithelial–mesenchymal transition (EMT), suppresses cytotoxic lymphocytes, and undermines ICI efficacy. This review article summarizes recent publications about plasma-derived exosomes from HNSCC patients. These exosomes carry tumor and immune checkpoint markers, reflect tumor burden and treatment response, and strongly modulate immune cells by suppressing T- and B-cell activity and promoting immunosuppressive macrophages. We encourage functional and biomechanistic future studies in the field of HNSCC that examine how CAF subtypes exosomes achieve an immunoresistant TME. Full article

The introduction of immune checkpoint inhibitors (ICIs) as a part of immunotherapy represented a therapeutic breakthrough in the landscape of cancer treatment. The action of these inhibitors consists of blocking certain inhibitory receptors in the immune system. Blocking these inhibitory pathways, ICIs induce an enhanced T cell-mediated response necessary to neutralize tumor cells. Over the last 10 years, programmed death cell protein1 (PD-1), PD ligand 1 (PD-L1), and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) have been among the inhibitory receptors most targeted by ICIs. Currently, this innovative therapeutic approach faces two major challenges: early identification of cancer patients who are likely to get a significant therapeutic benefit through the use of these inhibitors, and the second challenge is the early prediction of likely immune-related adverse events (irAEs) associated with such therapy. The aim of the present text is to discuss the current research efforts to discover and develop much needed effective biomarkers, which may represent an important step towards more efficient and risk-free immunotherapy. We also highlight the increasing role in clinical analyses of liquid biopsy sampling combined with mass spectrometry-based proteomics and how such combination is contributing to current research efforts to enhance the role of immunotherapy. Full article

Beta-arrestin 1 (ARRB1) is a multifunctional adaptor protein that regulates diverse signaling pathways beyond its canonical role in G-protein-coupled receptor desensitization. While ARRB1 has been implicated in cancer progression, its role in modulating host immunity against multiple myeloma (MM) remains unexplored. Here, we demonstrate that host ARRB1 deficiency significantly enhances anti-myeloma immunity and prolongs survival in a syngeneic murine MM model. Using Vk*MYC myeloma cells transplanted into wild-type and ARRB1 knockout mice, we show that ARRB1 deficiency in the host microenvironment promotes robust T cell infiltration and activation while reducing immunosuppressive myeloid populations. Notably, ARRB1 knockout mice exhibited markedly decreased programmed cell death protein-1 (PD-1) expression on both T cells and myeloid-derived suppressor cells, indicating reduced immune exhaustion. Furthermore, ARRB1 deficiency conferred protection against myeloma-induced bone disease, suggesting a dual role in immune regulation and bone homeostasis. These findings establish ARRB1 as a critical negative regulator of host anti-myeloma immunity and identify it as a potential therapeutic target for enhancing immunotherapy efficacy in MM. Full article

Oral and oropharyngeal squamous cell carcinomas (OSCC and OPSCC), two major sub-types of Head and Neck cancer, remain associated with significant morbidity and exhibit poor prognosis, with limited response to conventional therapies in advanced stages. Recent therapeutic strategies have increasingly focused on molecular targets involved in tumor proliferation, angiogenesis, and immune evasion. This overview provides a concise synthesis of targeted therapies under investigation or already in clinical use, including monoclonal antibodies against epidermal growth factor receptor (EGFR) (e.g., cetuximab) and immune checkpoint inhibitors (e.g., nivolumab, pembrolizumab), as well as inhibitors of programmed cell death protein 1 (PD-1) and its ligand (PD-L1) or agents targeting angiogenic and intracellular signaling pathways such as VEGF and mTOR. Alongside these novel agents, growing interest surrounds the repurposing of established pharmacological agents which appear to modulate tumor-related inflammation, metabolic dysregulation, and epithelial-to-mesenchymal transition. Metformin and statins, for instance, have demonstrated anti-proliferative and pro-apoptotic effects in preclinical OSCC models. Notably, recent evidence suggests that regular use of nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, may improve survival specifically in patients with PIK3CA-altered Head and Neck tumors, potentially through modulation of the COX-2/PGE2 axis. Although prospective evidence remains limited and somewhat heterogeneous, existing preclinical and observational studies suggest that these agents may improve survival and reduce treatment-related toxicity, further pointing to the relevance of molecular stratification in guiding future repurposing strategies. This article aims to map the current therapeutic landscape, highlighting both established molecular targets and emerging repositioned drugs in the management of OSCC and OPSCC. Full article

Primary glomerulopathies share common immune dysregulation but differ in their predominant pathways. We compared immune checkpoint profiles in minimal change disease (MCD) and membranous nephropathy (MN) with those in healthy volunteers (HV). In a cohort of 90 individuals (MCD, n = 30; MN, n = 30; HV, n = 30), we performed multiparameter flow cytometry of PBMCs to assess the expression of PD-1/PD-L1, CTLA-4/CD86, and CD200/CD200R on CD4+and CD8+ T cells, CD19+ B cells, and natural killer cells (NK cells). ELISA measured serum soluble checkpoint concentrations, and transcript levels in PBMCs were measured by qPCR. Nonparametric statistics and ROC analysis were used. In MCD, a skewed T cell pattern was observed, characterized by dominant expression of PD-1 and CTLA-4, whereas in MN, a humoral predominance was observed with higher PD-L1 expression and attenuated CD200/CD200R axis. Across diseases, expression profiles and correlations between markers differed between HV and between MCD and MN. Soluble checkpoints (sPD-1, sPD-L1, sCD200, sCD200R) showed potential discriminatory value for GN compared to HV and for differentiating MCD from MN in ROC analyses. These findings indicate that the mechanisms maintaining immune tolerance in primary GN are standard but pathway-specific, consistent with the dominant immunological component of each disease. A significant implication of this study is the need to conduct tissue-level studies to confirm clinical utility and provide insights into personalized immunomodulatory strategies targeting PD-1/PD-L1, CTLA-4/CD86, and CD200/CD200R. Full article

Background and Clinical Significance: Immune checkpoint inhibitors (ICIs), a revolutionary class of oncology therapeutics that enhance T cell-mediated antitumor immunity, are associated with various immune-related adverse events (IRAEs). While destructive thyroiditis and hypothyroidism are common, ICI-induced Graves’ disease (GD) is exceedingly rare, and the occurrence of concomitant Graves’ ophthalmopathy (GO) is even rarer. Case Presentation: A 57-year-old man with bladder cancer developed GO after receiving the first dose of the programmed death 1 (PD-1) inhibitor pembrolizumab. He presented with severe proptosis, extraocular muscle enlargement, hyperthyroidism, and significantly increased thyroid-stimulating hormone receptor autoantibodies (TRAb). Following the treatment with glucocorticoids and immunosuppressive therapy, his symptoms improved markedly but relapsed upon dosage reduction. To date, we have not identified any previous reports of GO with confirmed positive thyroid-related antibodies induced by pembrolizumab. Conclusions: This case offers valuable insights into the potential IRAEs, underscoring the importance of thorough clinical evaluation and early recognition to improve patient outcomes and quality of life. A literature review of ICI-induced GO was also performed, with further discussion of the potential pathogenic mechanisms, risk factors, and management strategies. Full article

Background: Endometriosis, believed by many to be rooted in immunology, is a chronic disease. Upregulation of programmed cell death protein 1 (PD-1) in immune cells may compromise their defensive function, a mechanism demonstrated in the context of cancer spread. This study aims to explore the potential involvement of PD-1 in the pathophysiology and progression of endometriosis. A total of 62 patients who underwent laparoscopic surgery were analyzed, with 47 diagnosed with endometriosis and 15 serving as controls. We collected peritoneal fluid and peripheral blood samples during surgery and examined them using flow cytometry. Using a panel of monoclonal antibodies, the samples were stained and the expression of PD-1 in immune cells was evaluated. Results: We observed a statistically significant rise in the percentage of the CD56⁺ CD16⁺ NK cell subset expressing PD-1 within the peritoneal fluid of endometriosis patients compared to the control group (p = 0.021). Similarly, we found that PD-1 expression on immune cells significantly differed based on factors such as body mass index and smoking habits. Moreover, peritoneal subsets of PD-1⁺ T and NK cells showed an increase in patients presenting symptomatic endometriosis and those with more widespread disease. Conclusions: Our evaluation of the inhibitory PD-1 receptor has strengthened the potential connection between immune escape mechanisms often seen in cancer cells and those in endometriotic cells. This concept could pave the way for future research in the field of immunomodulation and endometriosis. Full article

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

Skin cancer is the most common cancer worldwide. The incidence of skin cancer has been increasing worldwide. Nearly 75% of all skin cancers are basal cell carcinomas (BCC), cutaneous squamous cell carcinoma (cSCC) represents approximately 20%, and those remaining are melanomas (4%) or other rare tumors (1%). Given the high cure rates and the ability to histologically confirm tumor clearance, surgical therapy is the gold standard for the treatment of skin cancer. Conventional surgery is the most employed technique for the removal of non-melanoma skin cancer (NMSCs). Mohs Micrographic Surgery (MMS) is the most precise surgical method for the treatment of non-melanoma skin cancer, allowing for 100% margin evaluation, being the gold-standard method for surgical treatment of non-melanoma skin cancer. Whenever it is possible to obtain wide margins (4 to 6 mm), cure rates vary from 70% to 99%. Imiquimod, a synthetic imidazoquinolinone amine, is a topical immune response modifier approved by the U.S. Food and Drug Administration (FDA) for the treatment of external anogenital warts, actinic keratosis (AK), and superficial basal cell carcinoma (sBCC). The efficacy of imiquimod is primarily attributed to its ability to modulate both innate and adaptive immune responses, as well as its direct effects on cancer cells. Imiquimod exerts its immunomodulatory effects by activating Toll-like receptors 7 and 8 (TLR7/8) on various immune cells, including dendritic cells, macrophages, and natural killer (NK) cells. Upon binding to these receptors, imiquimod triggers the MyD88-dependent signaling pathway, leading to the activation of nuclear factor kappa B (NF-κB) and interferon regulatory factors (IRFs). This cascade leads to the production of pro-inflammatory cytokines, including interferon-alpha (IFN-α), tumor necrosis factor-alpha (TNF-α), interleukin-12 (IL-12), and interleukin-6 (IL-6). These cytokines enhance local inflammation, recruit additional immune cells to the tumor site, and stimulate antigen presentation, thereby promoting an anti-tumor immune response. Radiation therapy (RTh) may be employed as a primary treatment to BCC. It may also be employed as an adjuvant treatment to surgery for SCC and aggressive subtypes of BCC. RTh triggers both direct and indirect DNA damage on cancer cells and generates reactive oxygen species (ROS) within cells. ROS trigger oxidative damage to DNA, proteins, and lipids, exacerbating the cellular stress and contributing to tumor cell death. Recently, immunotherapy emerged as a revolutionary treatment for all stages of SCC. Cemiplimab is a human programmed cell death 1 (PD-1)-blocking antibody that triggers a response to over 50% of patients with locally advanced and metastatic SCC. A randomized clinical trial (RCT) published in 2022 revealed that cemiplimab was highly effective in the neoadjuvant treatment of large SCCs. The drug promoted a significant tumor size decrease, enabling organ-sparing operations and a much better cosmetic effect. A few months ago, a RCT of cemiplimab on adjuvant therapy for locally aggressive SCC was published. Interestingly, cemiplimab was administered to patients with local or regional cutaneous squamous cell carcinoma after surgical resection and postoperative radiotherapy, at high risk for recurrence owing to nodal features, revealed that cemiplimab led to much lower risks both of locoregional recurrence and distant recurrence. Full article