Search Results (598)

Background: Secondary rejection remains a major obstacle in skin allografting. Some viruses, such as human herpesvirus and cytomegalovirus, evade immune detection through proteins like the unique short glycoprotein 11 (US11), which down-regulates major histocompatibility complex (MHC) class I expression. This study explores the use of recombinant US11 protein as a biopharmaceutical approach to reduce MHC-I expression and thus decrease alloreactivity in human primary keratinocytes. Methods: Human keratinocytes were treated with recombinant US11 protein, and MHC-I expression was assessed via Western blot and flow cytometry. To evaluate immunomodulatory effects, US11-stimulated keratinocytes were co-cultured with peripheral blood mononuclear cells (PBMCs), and interferon-gamma (IFN-γ) levels were measured by ELISA. Additionally, ex vivo human skin tissue was stimulated with US11 to assess long-term MHC-I modulation. Results: US11 treatment significantly reduced MHC-I surface expression in keratinocytes. Co-cultures showed decreased IFN-γ secretion, indicating lower T cell activation. Human skin tissue stimulated with US11 exhibited reduced MHC-I expression after 7 days. Conclusions: This proof-of-concept study suggests that recombinant US11 protein may serve as an effective biopharmaceutical to reduce keratinocyte immunogenicity. Further in vitro and in vivo studies are warranted to validate its potential for clinical application in skin transplantation. Full article

The endangered Bengal slow loris (Nycticebus bengalensis) relies heavily on captive/rescue populations for conservation. This study investigated the critical link between Major Histocompatibility Complex (MHC) class II DRB1 exon 2 (DRB1e2) genetic variation and gut microbiota in 46 captive individuals, aiming to improve ex situ management. Using standardized conditions across three enclosure types, we characterized DRB1e2 polymorphism via targeted sequencing and analyzed fecal microbiota using 16S rRNA gene amplicon sequencing. Results demonstrated that high DRB1e2 polymorphism significantly reduced microbial community evenness. Specific genotypes showed distinct microbial associations: G9 strongly correlated with beneficial short-chain fatty acid producers like Fructobacillus, and G2 positively correlated with Bifidobacterium spp., while G2, G3, and G4 correlated negatively with Buchnera (a nutrient-provisioning symbiont). Genotypes and polymorphism collectively explained 9.77% of microbiota variation, exceeding the weaker (5.15%), though significant, influence of enclosure type on β-diversity. These findings reveal that host DRB1e2 variation is a primary driver shaping gut microbiota structure and taxon abundance in captive slow lorises, providing evidence for MHC-mediated host–microbe co-adaptation. This offers a genetically informed framework for optimizing conservation strategies, such as tailoring diets or probiotics to specific genotypes, to enhance gut health and population viability. Full article

Oncolytic herpes simplex virus (oHSV) is a promising cancer immunotherapy that induces tumor cell lysis and stimulates anti-tumor immunity. Our previous single-cell RNA sequencing analysis of oHSV-treated medulloblastoma tumors revealed expansion and activation of tumor-infiltrating dendritic cells (DCs), and direct oHSV infection of DCs within the brain. While the therapeutic effects of oHSVs have been primarily attributed to tumor cell infection, we hypothesize that direct infection of DCs also contributes to therapeutic efficacy by promoting DC maturation and immune activation. Although the oHSV infection in DCs was abortive, it led to increased expression of major histocompatibility complex (MHC) class I/II and co-stimulatory molecules. oHSV-infected DCs activated naïve CD4⁺ and CD8⁺ T cells, inducing expression of CD69 and CD25. These primed T cells exhibited enhanced cytotoxicity against CT-2A glioma cells. Adoptive transfer of oHSV-infected DCs via subcutaneous injection near inguinal lymph nodes delayed tumor growth in a syngeneic CT-2A glioma model, independent of tumor viral replication and lysis. Mechanistically, our in vitro studies demonstrate that oHSV can directly infect and functionally activate DCs, enabling them to prime effective anti-tumor T cell responses. This study highlights the anti-tumor potential of leveraging oHSV-infected DCs to augment viroimmunotherapy as a cancer therapeutic. Full article

Major histocompatibility complex class I (MHC-I)-mediated antigen presentation plays a pivotal role in anti-tumor immunity by enabling CD8⁺ T cells to recognize and eliminate malignant cells. In melanoma, modulation of this pathway is critical for improving the efficacy of immunotherapies. Our study demonstrates that the natural compound Cepharanthine (CEP) exhibits notable antitumor activity by enhancing MHC-I-mediated antigen presentation. CEP treatment upregulated MHC-I expression (both membrane-bound and total levels) in melanoma cells in a concentration-dependent manner, thereby improving antigen-presenting capacity. Interestingly, when autophagy was pharmacologically blocked using Bafilomycin A1, co-treatment with CEP did not lead to further elevation of MHC-I expression, suggesting that CEP’s effect is mediated through disruption of the autophagic pathway. Mechanistically, CEP induced autophagosome accumulation, as evidenced by an increase in GFP-LC3 puncta. Fluorescence imaging further confirmed that CEP selectively impaired lysosomal acidification without affecting autophagosome–lysosome fusion, thereby inhibiting late-stage autophagic flux. Furthermore, CEP treatment promoted CD8⁺ T cell infiltration into tumor tissues and enhanced the antitumor efficacy of anti-PD-1 therapy, resulting in greater tumor suppression compared to either treatment alone. The study elucidates how CEP’s selective lysosomal inhibition creates a tumor microenvironment more susceptible to immune surveillance, primarily through preserved MHC-I surface expression and subsequent T cell recognition. This work highlights CEP as a promising immunomodulatory agent and provides a potential strategy for improving the outcomes of immune checkpoint blockade therapy. Full article

Background: Anti-programmed death 1 receptor (PD-1) therapy is a promising treatment strategy for patients with unresectable advanced or recurrent gastric/gastroesophageal junction (G/GEJ) cancer. However, its response rate and survival benefits are still limited; an immunological analysis of the residual tumor after anti-PD-1 therapy would be important. Methods: We evaluated the clinical efficacy of tumor resection (TR) after chemotherapy or anti-PD-1 therapy in patients with unresectable advanced or recurrent G/GEJ cancer and analyzed the immune status of tumor microenvironment (TME) by immunohistochemistry using their surgically resected specimens. Results: Patients treated with TR after anti-PD-1 therapy had significantly longer survival compared to those treated with chemotherapy and anti-PD-1 therapy alone. Expression of human leukocyte antigen (HLA) class I and major histocompatibility complex (MHC) class II on tumor cells was markedly downregulated after anti-PD-1 therapy compared to chemotherapy. Furthermore, the downregulation of HLA class I may be associated with the activation of transforming growth factor-β signaling pathway in the TME. Conclusions: Immune escape from cytotoxic T lymphocytes may be induced in the TME in patients with unresectable advanced or recurrent G/GEJ cancer after anti-PD-1 therapy due to the downregulation of HLA class I and MHC class II expression on tumor cells. TR may be a promising treatment strategy for these patients when TR is feasible after anti-PD-1 therapy. Full article

Conventional immunotherapy, including immune checkpoint blockade and chimeric antigen receptor (CAR)-T cells, has revolutionized cancer therapy over the past decade. Yet, the efficacy of these therapies is limited by tumor resistance, antigen escape mechanisms, poor persistence, and T-cell exhaustion, particularly in the treatment of solid tumors. The emergence of unconventional immunotherapies offers novel opportunities by leveraging diverse immune cell subsets and synthetic biologics. This review explores various immunotherapy platforms, including gamma delta T cells, invariant natural killer T cells, mucosal-associated invariant T cells, engineered regulatory T cells, and universal CAR platforms. Additionally, it expands on biologics, including bispecific and multispecific antibodies, cytokine fusions, agonists, and oncolytic viruses, showcasing their potential for modular engineering and off-the-shelf applicability. Distinct features of unconventional platforms include independence from the major histocompatibility complex (MHC), tissue-homing capabilities, stress ligand sensing, and the ability to bridge adaptive and innate immunity. Their compatibility with engineering approaches highlights their potential as scalable, efficient, and cost-effective therapies. To overcome translational challenges such as functional heterogeneity, immune exhaustion, tumor microenvironment-mediated suppression, and limited persistence, novel strategies will be discussed, including metabolic and epigenetic reprogramming, immune cloaking, gene editing, and the utilization of artificial intelligence for patient stratification. Ultimately, unconventional immunotherapies extend the therapeutic horizon of cancer immunotherapy by breaking barriers in solid tumor treatment and increasing accessibility. Continued investments in research for mechanistic insights and scalable manufacturing are key to unlocking their full clinical potential. Full article

Schizophrenia is a challenging multifactorial neuropsychiatric disease that involves interactions between genetic susceptibility and environmental insults. Increasing evidence implicates viral infections as significant environmental contributors, particularly during sensitive neurodevelopmental periods. This review synthesises current findings on the viral hypothesis of schizophrenia, encompassing a wide array of neurotropic viruses, including influenza viruses, herpesviruses (HSV-1 and 2, CMV, VZV, EBV, HHV-6 and 8), hepatitis B and C viruses, HIV, HERVs, HTLV, Zika virus, BoDV, coronaviruses (including SARS-CoV-2), and others. These pathogens can contribute to schizophrenia through mechanisms such as direct microinvasion, persistent central nervous system infection, immune-mediated neuroinflammation, molecular mimicry, and the disturbance of the blood–brain barrier. Prenatal exposure to viral infections can trigger maternal immune activation, resulting in cytokine-mediated alterations in the neurological development of the foetus that persist into adulthood. Genetic studies highlight the role of immune-related loci, including major histocompatibility complex polymorphisms, in modulating susceptibility to infection and neurodevelopmental outcomes. Clinical data also support the “mild encephalitis” hypothesis, suggesting that a subset of schizophrenia cases involve low-grade chronic neuroinflammation. Although antipsychotics have some immunomodulatory effects, adjunctive anti-inflammatory therapies show promise, particularly in treatment-resistant cases. Despite compelling associations, pathogen-specific links remain inconsistent, emphasising the need for longitudinal studies and integrative approaches such as viromics to unravel causal relationships. This review supports a “multi-hit” model in which viral infections interfere with hereditary and immunological susceptibilities, enhancing schizophrenia risk. Elucidating these virus–immune–brain interactions may facilitate the discovery of biomarkers, targeted prevention, and novel therapeutic strategies for schizophrenia. Full article

Adoptive cell therapies have transformed the treatment landscape for hematologic malignancies. Yet, translation to solid tumors remains constrained by antigen heterogeneity, an immunosuppressive tumor microenvironment (TME), and poor persistence of conventional CAR-T cells. In response, innate immune cell platforms, particularly chimeric antigen receptor–engineered natural killer (CAR-NK) cells and chimeric antigen receptor–macrophages (CAR-MΦ), have emerged as promising alternatives. This review summarizes recent advances in the design and application of CAR-NK and CAR-MΦ therapies for solid tumors. We highlight key innovations, including the use of lineage-specific intracellular signaling domains (e.g., DAP12, 2B4, FcRγ), novel effector constructs (e.g., NKG7-overexpressing CARs, TME-responsive CARs), and scalable induced pluripotent stem cell (iPSC)-derived platforms. Preclinical data support enhanced antitumor activity through mechanisms such as major histocompatibility complex (MHC)-unrestricted cytotoxicity, phagocytosis, trogocytosis, cytokine secretion, and cross-talk with adaptive immunity. Early-phase clinical studies (e.g., CT-0508) demonstrate feasibility and TME remodeling with CAR-MΦ. However, persistent challenges remain, including transient in vivo survival, manufacturing complexity, and risks of off-target inflammation. Emerging combinatorial strategies, such as dual-effector regimens (CAR-NK⁺ CAR-MΦ), cytokine-modulated cross-support, and bispecific or logic-gated CARs, may overcome these barriers and provide more durable, tumor-selective responses. Taken together, CAR-NK and CAR-MΦ platforms are poised to expand the reach of engineered cell therapy into the solid tumor domain. Full article

Background/Objectives: Chimeric antigen receptor T-cell (CAR-T) therapy is a novel form of adoptive cellular immunotherapy that involves modifying autologous T cells to recognize and target tumor-associated antigens (TAAs) on malignant cells, independent of major histocompatibility complex (MHC) restriction. Although CAR-T therapy has shown remarkable success in treating hematologic malignancies, its efficacy in solid tumors remains limited, largely due to the lack of tumor-specific antigens and the complexity of the tumor microenvironment. This review aims to explore the rationale for continuing the development of adoptive cellular therapies in head and neck cancer (HNC), offering insights into the diagnostic and therapeutic challenges associated with this heterogeneous group of malignancies. Methods: We conducted a comprehensive literature review using the PubMed database to identify relevant studies on the application of CAR-T cell therapy in the management of HNC. Results: HNC presented numerous barriers to CAR-T cell infiltration, primarily due to the unique characteristics of its tumor microenvironment (TME). The TME in HNC is notably immunosuppressive, with a lymphocytic infiltrate predominantly composed of regulatory T cells (Tregs) and natural killer (NK) cells. These immune cells typically exhibit low expression of the CD16 receptor, which plays a crucial role in mediating antibody-dependent cellular cytotoxicity (ADCC), thereby limiting the effectiveness of CAR-T cell therapy. Conclusions: This comprehensive review suggests a potential clinical applicability of CAR-T therapy in HNC management. Full article

Endometrial stromal cells (EnSCs) undergo decidualization in response to progesterone. Decidualization facilitates spiral artery remodeling, immune tolerance in the endometrium, and fetal cell invasion and placentation—all essential for successful embryo implantation. Therefore, we aimed to investigate whether ergothioneine (EGT) plays a role in reproduction, particularly in decidualization and implantation. In this study, we found that solute carrier family 22 member 4 (SLC22A4), a specific transporter of EGT—a functional food ingredient with strong anti-aging properties—is upregulated in decidualized EnSCs. The effects of EGT were examined using uterine tissues from patients, primary cultured EnSCs, EnSC cell lines, and co-cultures with a fetal cell line. We observed a significant increase in SLC22A4 expression in secretory-phase human uterine tissue, decidualized EnSCs, and EnSC cell lines. We also found that EGT regulates insulin-like growth factor binding protein 1 expression, which promotes placentation. In co-cultures of EnSC and fetal cell lines, EGT upregulated ectonucleoside triphosphate diphosphohydrolase 1 and major histocompatibility complex, class I, G expression in fetal cell lines—both critical for placentation. These findings suggest that EGT is crucial to regulating decidualization and its markers, particularly insulin-like growth factor-binding protein 1, which contributes to placentation. Full article

The mammalian immune system, including key components such as toll-like receptors (TLRs), lymphocytes, and cytokines, plays a vital role in defending against diseases. In dogs, genetic polymorphisms and epigenetic regulation of immune-related genes contribute to breed-specific differences in susceptibility or resistance to infectious, autoimmune, and inflammatory diseases. Cytokines, essential for immune cell differentiation and activation, exhibit variable expression among breeds due to genetic factors like single-nucleotide polymorphisms (SNPs) and miRNA regulation. This variability influences immune responses not only to infections but also to chronic inflammatory conditions and cancer, providing insights for improved diagnosis, treatment, and breeding. Selective breeding has further shaped diverse immune phenotypes across breeds, especially through genetic variations in the major histocompatibility complex (MHC) region, which affect vulnerability to immune-mediated and immunodeficiency disorders. Recent studies emphasize the role of specific miRNAs in modulating immune responses during parasitic and viral infections, opening new avenues for precision veterinary medicine and immunotherapy. This review highlights the genetic and epigenetic regulation of immune genes in dogs and explores their potential applications in advancing veterinary diagnostics, therapeutics, and breeding strategies to enhance canine health. Full article

BAP31, a transmembrane protein in the endoplasmic reticulum, is known for its oncogenic properties, but its role in immunotherapy is not well understood. While BAP31’s involvement in liver, gastric, and cervical cancers has been documented, its role in pan-cancer immune regulation, particularly in breast cancer, remains unexplored. Using TCGA data, analysis via the Xiantao academic and GEPIA2 database showed that BAP31 upregulation correlates with advanced clinical stages and a poor prognosis. ROC analysis demonstrated BAP31’s high accuracy in distinguishing cancerous tissue from normal tissues. Additionally, BAP31 expression is associated with CNV, methylation, TMB, and MSI. In breast cancer, TIMER database analysis revealed that BAP31 expression is inversely correlated with the infiltration levels of myeloid-derived suppressor cells (MDSCs), macrophages, T lymphocytes, B lymphocytes, and neutrophils. Additionally, we investigated the relationship between BAP31 and the expression of major histocompatibility complex (MHC) molecules and chemokine receptors utilizing the TISIDB database. LinkedOmics analysis demonstrated associations between BAP31 and various immune-inflammatory pathways, while also indicating a negative correlation between BAP31 expression and four critical pathways: extracellular matrix receptor interaction, focal adhesion, JAK-STAT signaling, and TGF-β signaling. Furthermore, loss-of-function experiments employing shRNA-mediated knockdown of BAP31 resulted in a marked reduction in cell proliferation and an increase in apoptosis in breast cancer cells, thereby confirming its role in tumor promotion. These findings suggest that BAP31 may serve as a promising prognostic biomarker and a potential target for immunotherapy in breast cancer. Full article

Malignant tumors of the digestive system are widespread and pose a serious threat to humans. Immune escape is an important factor promoting the deterioration of malignant tumors in the digestive system. Natural killer cells (NK cells) are key members of the anti-tumor and immune surveillance system, mainly exerting cytotoxic effects by binding to the activating receptor natural killer cell group 2D (NKG2D) on their cell surface with the corresponding ligands (major histocompatibility complex class I chain-related protein A/B, MICA/B) on the surface of tumor cells. Malignant tumors of epithelial origin usually highly express NKG2D ligands such as MICA, which can attract NK cells to kill tumor cells and also serve as an important basis for NK cell-based immunotherapy. Tumor cells highly express hypoxia-inducible factor-1α (HIF-1α), which promotes the expression of matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinases (ADAMs). These metalloproteinases hydrolyze MICA and other ligands on the surface of tumor cells to generate soluble molecules. These soluble ligands, when binding to NKG2D, cannot activate NK cells and also block the binding of NKG2D to MICA on the surface of tumor cells, enabling tumor cells to evade the killing effect of NK cells. Almost all organs in the digestive system originate from epithelial tissue, so the soluble ligands generated by the HIF-1α/MMPs or HIF-1α/ADAMs signaling pathways play a crucial role in evading NK cell killing. A comprehensive understanding of this immune escape process is helpful for a deeper understanding of the molecular mechanism of NK cell anti-tumor activity. This article reviews the molecular mechanisms of common digestive system malignancies evading NK cell killing, providing new insights into the mechanism of tumor immune escape. Full article

The DNA-damage response (DDR) network and the immune system are significant mechanisms linked to the normal functioning of living organisms. Extensive observations suggest that agents that damage the DNA can boost immunity in various ways, some of which may be useful for immunotherapeutic applications. Indeed, the immune system can be activated by the DDR network through a number of different mechanisms, such as via (a) an increase in the tumor neoantigen burden, (b) the induction of the stimulator of interferon genes pathway, (c) the triggering of immunogenic cell death, (d) an increase in antigen presentation as a result of the augmented expression of the major histocompatibility complex type I molecule, (e) modification of the cytokine milieu in the tumor microenvironment, and (f) altered expression of the programmed cell death ligand-1. Together, the DDR network may improve the effect of immunostimulatory anticancer agents and provide a basis for devising more efficient treatment strategies, such as combinatorial therapies of DDR targeting drugs and immunomodulators. Here, the molecular mechanisms underlying the immune system’s activation by DDR are summarized, along with some of their possible uses in cancer treatment. Full article

Solid tumors pose significant therapeutic challenges due to their resistance to conventional treatments and the complexity of the tumor microenvironment. Cell-based immunotherapies offer a promising approach, enabling precise, personalized treatment through immune system modulation. This review explores several emerging cellular therapies for solid tumors, including tumor-infiltrating lymphocytes, T cell receptor-engineered T cells, CAR T cells, CAR natural killer cells, and macrophages. Tumor-infiltrating lymphocytes and their modified versions, T cell receptor-engineered T cells and CAR T cells, provide personalized immune responses, although their effectiveness can be limited by factors like variation in tumor antigens and the suppressive nature of the tumor environment. Natural killer cells engineered with chimeric receptors offer safer, non-major histocompatibility complex-restricted targeting, while modified macrophages exploit their natural ability to enter tumors and reshape the immune landscape. CAR-modified macrophages and macrophages conjugated with drugs are also considered as therapy for solid tumors. The review also examines the implications of autologous versus allogeneic cell sources. Autologous therapies ensure immunologic compatibility but are limited by scalability and manufacturing constraints. Allogeneic approaches offer “off-the-shelf” potential but require gene editing to avoid immune rejection. Integrating synthetic biology, gene editing, and combinatorial strategies will be essential to enhance efficacy and expand the clinical utility of cellular immunotherapies for solid tumors. Full article