Search Results (877)

Human leukocyte antigen class I (HLA-I) molecules present intracellular peptides on the cell surface to enable CD8+ T cells to effectively control viral infections. Many viruses disrupt this antigen presentation pathway to evade immune detection. In this study, we demonstrate that SARS-CoV-2 Nsp1 impairs both the constitutive and interferon-γ (IFN-γ)-induced upregulation of HLA-I. Moreover, Nsp1 also blocks IFN-γ-induced expression of HLA-II. We found that, contrary to previously published work, the early SARS-CoV-2 B 1.1.7 Alpha variant lacking the accessory protein ORF8 retained full capacity to downregulate HLA-I, comparable to an ORF8-expressing wild-type isolate. While ectopic overexpression of ORF8 could reduce HLA-I surface levels, this effect was only observed at high expression levels. In contrast, moderate expression of the viral protein Nsp1 was sufficient to potently suppress both basal and IFN-γ-induced HLA-I, as well as HLA-II expression. To probe the underlying mechanism, we analyzed HLA-I-associated genes in previously published RNA-sequencing datasets and confirmed that Nsp1 reduces expression of components required for HLA-I biosynthesis and antigen processing. These findings identify Nsp1 as a key factor that impairs antigen presentation pathways, potentially contributing to the ability of SARS-CoV-2 to modulate immune recognition. Full article

Type 1 diabetes mellitus (T1DM) is a chronic autoimmune disorder characterized by the destruction of insulin-producing pancreatic beta cells, resulting in lifelong insulin dependence. While genetic susceptibility—particularly human leukocyte antigen (HLA) class II alleles—is a major risk factor, accumulating evidence implicates viral infections as potential environmental triggers in disease onset and progression. This narrative review synthesizes current findings on the role of viral pathogens in T1DM pathogenesis. Enteroviruses, especially Coxsackie B strains, are the most extensively studied and show strong epidemiological and mechanistic associations with beta-cell autoimmunity. Large prospective studies—including Diabetes Virus Detection (DiViD), The environmental determinans of diabetes in the young (TEDDY), Miljøfaktorer i utvikling av type 1 diabetes (MIDIA), and Diabetes Autoimmunity Study in the Young (DAISY)—consistently demonstrate correlations between enteroviral presence and the initiation or acceleration of islet autoimmunity. Other viruses—such as mumps, rubella, rotavirus, influenza A (H1N1), and SARS-CoV-2—have been investigated for their potential involvement through direct cytotoxic effects, immune activation, or molecular mimicry. Interestingly, certain viruses like varicella-zoster virus (VZV) and cytomegalovirus (CMV) may exert modulatory or even protective influences on disease progression. Proposed mechanisms include direct beta-cell infection, molecular mimicry, bystander immune activation, and dysregulation of innate and adaptive immunity. Although definitive causality remains unconfirmed, the complex interplay between genetic predisposition, immune responses, and viral exposure underscores the need for further mechanistic research. Elucidating these pathways may inform future strategies for targeted prevention, early detection, and vaccine or antiviral development in at-risk populations. Full article

Glioblastoma (GBM) is a highly aggressive and heterogeneous brain tumor. Glioma stem-like cells (GSCs) play a central role in tumor progression, therapeutic resistance, and recurrence. Although immune cells are known to shape the GBM microenvironment, the impact of antigen-presenting-cell (APC) signature genes on tumor-intrinsic phenotypes remains underexplored. We analyzed both bulk- and single-cell RNA sequencing datasets of GBM to investigate the association between APC gene expression and tumor-cell states, including stemness and metabolic reprogramming. Signature scores were computed using curated gene sets related to APC activity, KEGG metabolic pathways, and cancer hallmark pathways. Protein–protein interaction (PPI) networks were constructed to examine the links between immune regulators and metabolic programs. The high expression of APC-related genes, such as HLA-DRA, CD74, CD80, CD86, and CIITA, was associated with lower stemness signatures and enhanced inflammatory signaling. These APC-high states (mean difference = –0.43, adjusted p < 0.001) also showed a shift in metabolic activity, with decreased oxidative phosphorylation and increased lipid and steroid metabolism. This pattern suggests coordinated changes in immune activity and metabolic status. Furthermore, TNF-α and other inflammatory markers were more highly expressed in the less stem-like tumor cells, indicating a possible role of inflammation in promoting differentiation. Our findings revealed that elevated APC gene signatures are associated with more differentiated and metabolically specialized GBM cell states. These transcriptional features may also reflect greater immunogenicity and inflammation sensitivity. The APC metabolic signature may serve as a useful biomarker to identify GBM subpopulations with reduced stemness and increased immune engagement, offering potential therapeutic implications. Full article

Stage IV colorectal cancer has a poor prognosis, and liver metastases are prone to recurrence, even after resection. This study aimed to identify common cancer antigens, using immunohistochemical staining, as promising targets for antigen-specific immunotherapies in colorectal cancer. We analyzed expression levels and intracellular localization of seven common cancer antigens, CLDN1, EphB4, LAT1, FOXM1, HSP105α, ROBO1, and SPARC, and human leukocyte antigen (HLA) class I via immunohistochemical staining of 85 surgical specimens from primaries and liver metastases. Staining intensity and positive staining were scored to evaluate antigen expression. In 25 primaries, seven cancer antigens were expressed in 88–96% of cases, while HLA class I was expressed on the cell membrane in 80.0% of cases. In 60 liver metastases, FOXM1 and SPARC expression were approximately half that observed in the primaries. Other antigens and HLA class I were highly expressed in both. Most of the primaries and liver metastases may benefit from chimeric antigen receptor-T cell therapy targeting CLDN1, EphB4, and LAT1. Cases with high HLA class I expression may be suitable for vaccine-based and T cell receptor-T cell therapy targeting CLDN1, EphB4, LAT1, FOXM1, HSP105α, ROBO1, and SPARC for primaries and targeting antigens, excluding FOXM1 and SPARC, for liver metastases. Full article

The emergence of anti-TNF agents has revolutionized the management of inflammatory bowel disease, yet a significant proportion of patients experience primary non-response or secondary loss of response due to immunogenicity. As the field of precision medicine advances, genetic predictors such as human leukocyte antigen (HLA) variants are gaining increasing attention. This review provides a comprehensive synthesis of current evidence on the role of HLA genotypes in inflammatory bowel disease susceptibility and disease behavior, with a focus on their mechanistic and clinical relevance in anti-TNF therapy. Special emphasis is placed on HLA-DQA1*05, a validated predictor of anti-drug antibody formation and reduced therapeutic durability. We explore the immunological basis of HLA-mediated immunogenicity, summarize pharmacogenetic and biomarker findings, and discuss how HLA typing may be integrated into treatment algorithms to improve patient stratification and long-term outcomes. As immunogenetics continues to inform clinical decision-making, understanding the interplay between HLA polymorphisms and therapeutic response offers new opportunities for biomarker-guided, personalized care in inflammatory bowel disease. Full article

Background: Pancreas and pancreas–kidney transplantation are well-established therapeutic options for patients with type 1 diabetes mellitus (T1DM) and end-stage kidney disease (ESKD), offering the potential to restore endogenous insulin production and kidney function. It improves metabolic control, quality of life, and long-term survival. While surgical techniques and immunosuppressive strategies have advanced considerably, graft rejection and limited long-term graft survival remain significant clinical challenges. Method: To better understand these risks, the genetic and immunological factors that influence transplant outcomes are examined. Beyond traditional human leukocyte antigen (HLA) matching, non-HLA genetic variants such as gene deletions and single-nucleotide polymorphisms (SNPs) have emerged as contributors to alloimmune activation and graft failure. Result: Polymorphisms in cytokine genes, minor histocompatibility antigens, and immune-regulatory pathways have been implicated in transplant outcomes. However, the integration of such genomic data into clinical practice remains limited due to underexplored gene targets, variability in study results, and the lack of large, diverse, and well-characterized patient cohorts. Initiatives like the International Genetics & Translational Research in Transplantation Network (iGeneTRAiN) are addressing these limitations by aggregating genome-wide data from thousands of transplant donors and recipients across multiple centers. These large-scale collaborative efforts aim to identify clinically actionable genetic markers and support the development of personalized immunosuppressive strategies. Conclusions: Overall, genetic testing and genomics hold great promise in advancing precision medicine in pancreas and pancreas–kidney transplantation. Full article

Anticytokine autoantibodies (AAbs), particularly anti-interferon-gamma (anti-IFN-γ) AAbs, disrupt cytokine functions, leading to infections, autoimmune-like diseases, and conditions resembling interleukin-12 (IL-12)/IFN-γ pathway defects. Advances in genetic testing have clarified overlaps between autoinflammatory, autoimmune disorders, and primary immunodeficiencies but reveal complex phenotypes and pathways. While these insights deepen our understanding of immune mechanisms, they also complicate diagnosis and treatment, with limited options for IFN-γ deficiencies caused by genetic mutations. The adult-onset immunodeficiency with disseminated lymphadenitis due to nontuberculous mycobacteria (NTM) and other opportunistic infections has been linked to high levels of anti-IFN-γ AAbs. This syndrome, initially identified in HIV-negative Asian patients, frequently affects individuals of Asian descent and may be associated with specific human leukocyte antigen (HLA) alleles. The presence of neutralizing anti-IFN-γ AAbs impairs the IFN-γ-dependent immune response, likely contributing to the persistent NTM infection. This study underscores the potential for late-onset anti-IFN-γ AAb syndrome to manifest with disseminated NTM (dNTM) infections, highlights the importance of timely diagnosis and considers rituximab as a potential therapeutic option. Full article

Background/Objectives: Organ transplantation is a life-saving intervention for patients with terminal organ failure, but long-term success is hindered by graft rejection and dependence on lifelong immunosuppressants. These drugs pose risks such as opportunistic infections and malignancies. Chimeric antigen receptor (CAR) technology, originally developed for cancer immunotherapy, has been adapted to regulatory T cells (Tregs) to enhance their antigen-specific immunosuppressive function. This systematic review evaluates the preclinical development of CAR-Tregs in promoting graft tolerance and suppressing graft-versus-host disease (GvHD). Methods: A systematic review following PROSPERO guidelines (CRD420251073207) was conducted across PubMed, Scopus, and Web of Science for studies published from 2015 to 2024. After screening 105 articles, 17 studies involving CAR-Tregs in preclinical or in vivo transplant or GvHD models were included. Results: CAR-Tregs exhibited superior graft-protective properties compared to unmodified or polyclonal Tregs. HLA-A2-specific CAR-Tregs consistently improved graft survival, reduced inflammatory cytokines, and suppressed immune cell infiltration across skin, heart, and pancreatic islet transplant models. The inclusion of CD28 as a co-stimulatory domain enhanced Treg function and FOXP3 expression. However, challenges such as Treg exhaustion, tonic signaling, and reduced in vivo persistence were noted. Some studies reported synergistic effects when CAR-Tregs were combined with immunosuppressants like rapamycin or tacrolimus. Conclusions: CAR-Tregs offer a promising strategy for inducing targeted immunosuppression in allogeneic transplantation. While preclinical findings are encouraging, further work is needed to optimize CAR design, ensure in vivo stability, and establish clinical-scale manufacturing before translation to human trials. Full article

High-grade serous ovarian cancer (HGSOC) is an aggressive gynecological malignancy characterized by intraperitoneal spread and chemotherapy resistance. Chemotherapies have demonstrated limited effectiveness in HGSOC, underscoring the urgent need to evaluate how the tumor microenvironment (TME) was reshaped by chemotherapy in different sites of tumor foci. In this study, we performed single-cell transcriptomic analysis to explore the TME in samples obtained from various sites of tumor foci, with or without the history of Neoadjuvant chemotherapy (NACT). We discovered that chemotherapy reshaped the tumor immune microenvironment, evident through the reduction in human leukocyte antigen (HLA) diversity and the increase in PDCD1/CD274 in CD8_ANXA1, LAMP3+ dendritic cell (DC_LAMP3), and EREG+ monocytes (mono_EREG). Moreover, cancer.cell.2, cancer-associated C3+ fibroblasts (CAF_C3), and Fibrocyte_CD34, which are prone to accumulate in the metastatic site and post-NACT group, harbored poor clinical outcome, reflected in the immune exclusion and tumor progression signaling. Cell–cell communication identified a stronger interaction between cancer.cell.2 and CAF_C3, as well as Fibrocyte_CD34, in post-NACT samples, indicating that chemotherapy reshapes pre-existing cell clusters in a site-dependent manner. Our findings suggest that chemotherapy and sites of foci were critical for the transcriptional reprogramming of pre-existed cell clusters. Our study offers a single-cell phenotype data substrate from which to develop a personalized combination of chemotherapy and immunotherapy. Full article

Background/Objectives: Head and neck squamous cell carcinoma (HNSCC) is the seventh most common cancer, with limited responsiveness to immune checkpoint inhibitors (ICIs). Cancer vaccine therapy is a promising novel immunotherapeutic approach that stimulates tumor-specific T cells. Receptor tyrosine kinase-like orphan receptor 1 (ROR1), which is overexpressed in malignant tumors but minimally expressed in normal tissues, presents a promising target for immunotherapy. This study aimed to evaluate ROR1 as a target for helper T lymphocyte (HTL)-based peptide vaccine immunotherapy in HNSCC. Methods: ROR1 expression in HNSCC tissues was assessed by immunohistochemistry. A novel ROR1-derived epitope (ROR1_403–417) was identified and used to generate ROR1-reactive HTLs. Functional assays measuring IFN-γ and granzyme B secretion, as well as direct cytotoxicity, were performed. The effects of ICIs on HTL activity were also examined. The presence of ROR1-reactive T cells in the peripheral blood of patients with HNSCC was evaluated. Results: ROR1 positivity rates in HNSCC tissues were significantly higher (80.0%) than those in healthy controls (16.7%), and high ROR1 expression correlated with advanced clinical stages. HTL lines recognized the ROR1_403–417 peptide in a human leukocyte antigen (HLA)-DR-restricted manner, secreted effector cytokines, and exhibited direct cytotoxicity against ROR1+ tumor cells. Dual PD-L1/PD-L2 blockade further enhanced HTL responses. ROR1-reactive T cells were detected in the peripheral blood of patients with HNSCC. Conclusions: ROR1 represents a promising target for immunotherapy in HNSCC. The ROR1_403–417 peptide can elicit ROR1-reactive HTLs that exhibit antitumor responses against HNSCC cell lines, which can be enhanced by ICIs. These findings support the potential of ROR1-targeted peptide vaccine therapy for HNSCC. Full article

The Bacillus Calmette-Guérin (BCG) vaccine confers broad, non-specific immunity that may bolster defenses against respiratory viruses. While NOD2 (nucleotide-binding oligomerization domain-containing protein 2)-driven pathways are central to innate immune responses, the contribution of surface receptor modulation on monocytes to shaping these responses remains underexplored. We analyzed whole-blood cultures from BCG-vaccinated Polish children, stratified by serostatus to SARS-CoV-2 and RSV, and stimulated for 48 h with live BCG, purified viral antigens, or both. RT-qPCR quantified mRNA levels of NOD2 and key cytokines (IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, TNF), while flow cytometry assessed CD14, HLA-DR, CD11b, and CD206 expression. Co-stimulation with BCG + RSV elicited the strongest transcriptional response, notably a 2–4-fold upregulation of NOD2, IL-1β, and IL-6 versus RSV alone. In SARS-CoV-2(+) donors, RSV alone induced higher NOD2 expression than BCG or BCG + RSV, while IL-2 peaked following BCG + SARS-CoV-2. Across conditions, NOD2 positively correlated with IL-4 and IL-6 but negatively correlated with IL-1β in SARS-CoV-2 cultures. Viral antigens increased CD14 and HLA-DR on monocytes, suggesting activation; CD206 rose only in dual-seropositive children. Our findings indicate that BCG stimulation affects pediatric antiviral immunity through NOD2-related cytokine production and induction of a CD14⁺HLA-DR⁺ phenotype, supporting its potential role in boosting innate defenses against respiratory pathogens. Full article

Background/Objectives: The physiological activation of cytotoxic CD8^pos T cells (CTLs) relies on the engagement of the TCR/CD3 complex with cognate peptide-HLA class I (pHLA-I) on target cells, triggering cell lysis with appropriate cytokine release and minimized off-target toxicity. In contrast, current immunotherapies for CD19-expressing hematological malignancies, such as chimeric antigen receptor (CAR) T cells and bispecific T cell engagers (BiTEs), bypass TCR/pHLA interactions, resulting in CTL hyperactivation and excessive cytokine release, which frequently cause severe immune-related adverse events (irAEs). Thus, there is a pressing need for T cell-based therapies that preserve physiological activation while maintaining antitumor efficacy. Methods: To address this, we developed CD19-ReTARG^TPR, a novel fusion protein consisting of the immunodominant cytomegalovirus (CMV) pp65-derived peptide TPRVTGGAM (TPR) covalently presented by a soluble HLA-B*07:02/β2-microglobulin complex fused to a high-affinity CD19-targeting Fab antibody fragment. The treatment of CD19-expressing cancer cells with CD19-ReTARG^TPR makes them recognizable for pre-existing anti-CMV_pp65 CTLs via physiological TCR-pHLA engagement. Results: Our preclinical data demonstrate that CD19-ReTARG^TPR efficiently redirects anti-CMV CTLs to eliminate CD19-expressing cancer cells, including both established cell lines and primary chronic lymphocytic leukemia (CLL) cells. Unlike CD19-directed CAR T cells or the CD19/CD3 BiTE blinatumomab, CD19-ReTARG^TPR mediated robust cytotoxic activity without triggering supraphysiological cytokine release. Importantly, this approach retained efficacy even against cancer cells with low CD19 expression. Conclusions: In summary, we provide a robust proof-of-concept study and show that CD19-ReTARG^TPR offers a promising alternative strategy for T cell redirection, enabling the selective and effective killing of CD19-expressing malignancies while minimizing cytokine-driven toxicities through physiological CTL activation pathways. Full article

Head and neck squamous cell carcinoma (HNSCC) is a highly heterogeneous malignancy characterized by a complex tumor microenvironment (TME) that plays a critical role in disease progression and therapeutic resistance. Tumor-infiltrating immune cells, including T lymphocytes, macrophages, dendritic cells, and myeloid-derived suppressor cells, exhibit dual functions, either promoting or suppressing tumor growth depending on their phenotype and interactions within the TME. The presence of immune evasion mechanisms, such as the loss of human leukocyte antigen (HLA) expression, upregulation of immune checkpoint molecules, and metabolic reprogramming (hypoxia-induced glycolysis and lactate accumulation), further contributes to immune suppression and poor treatment responses. While immune checkpoint inhibitors (ICIs) have revolutionized the treatment of recurrent/metastatic HNSCC, response rates remain highly variable, underscoring the need for biomarker-driven patient selection and combinatorial therapeutic strategies. This review provides a comprehensive analysis of the role of immune cells in the TME of HNSCC, discusses the mechanisms underlying immune escape, and explores emerging immunotherapeutic and epigenetic-targeting approaches aimed at enhancing antitumor immune responses and improving clinical outcomes. Full article

Chimeric antigen receptor (CAR)-engineered natural killer (NK) cells are a promising platform for off-the-shelf immunotherapy due to their safety advantages over CAR-T cells, including lower risk of graft-versus-host disease, cytokine release syndrome, and neurotoxicity. However, their persistence and efficacy are limited by immunological challenges such as host T-cell-mediated rejection, NK cell fratricide, and macrophage-mediated clearance. This review summarizes gene editing strategies to overcome these barriers, including β2-microglobulin (B2M) knockout and HLA-E overexpression to evade T and NK cell attacks, CD47 overexpression to inhibit phagocytosis, and TIGIT deletion to enhance cytotoxicity. In addition, we discuss functional enhancements such as IL-15 pathway activation, KIR modulation, and transcriptional reprogramming (e.g., FOXO1 knockout) to improve persistence and antitumor activity. We also highlight the role of induced pluripotent stem cell (iPSC)-derived NK platforms, enabling standardized, scalable, and multiplex gene-edited products. Finally, we explore artificial intelligence (AI) applications in immunogenomic profiling and predictive editing to tailor NK cell therapies to patient-specific HLA/KIR/SIRPα contexts. By integrating immune evasion, functional reinforcement, and computational design, we propose a unified roadmap for next-generation CAR-NK development, supporting durable and broadly applicable cell-based therapies. Full article

Background and Objectives: This study explores the immunogenetic associations of human leukocyte antigens (HLAs) and cytokine levels in people living with HIV/AIDS (PLWH) who exhibit HIV-related skin disorders. HIV-related skin disorders, including inflammatory eruptions, atopic and seborrheic dermatitis, psoriasis, and pruritic papular eruption, are common among PLWH. These conditions may be influenced by genetic and immunological factors. This study aims to investigate the associations between HLA class II alleles, cytokine levels, and the presence of HIV-related dermatoses, providing insights into genetic susceptibility and immune mechanisms. Materials and Methods: This study included 115 PLWH with HIV-related skin disorders and a control group of 80 healthy individuals. HLA allele frequencies were analyzed, and cytokine levels (IL-1β, IL-10, IFN-y) were measured in blood samples. Statistical analyses were performed to identify significant differences in allele frequencies and cytokine responses between the groups. Results: Risk alleles (DQB1*0201:0301, OR = 19.4 and DQA1*0101:0501, OR = 4.2) and protective alleles (DRB1*07:13, OR = 0.19, DRB1*01:13, OR = 0.09, DRB1*04:11, OR = 0.07, and DQA1*0501:0501, OR = 0.24) showed statistically significant differences in frequency (p < 0.05) between PLWH and healthy controls. The protective DQA1*0501:0501 allele was associated with elevated levels of IL-1β (p < 0.001, r = 0.79) and IL-10 (p = 0.010, r = 0.63). Increased IL-1β levels may enhance immune responses, while higher IL-10 levels may exert anti-inflammatory effects, potentially reducing susceptibility to HIV-related dermatoses. Regression analysis revealed that IL-1β (Exp(B) = 0.76, p < 0.001) and IFN-γ (Exp(B) = 1.06, p = 0.043) are significant predictors for the likelihood of developing HIV-related dermatoses. An increase in IL-1β levels reduced this likelihood by 24%, while an increase in IFN-γ levels increased it by 6%. Conclusions: The findings emphasize the interaction between HLA class II alleles and cytokine profiles in determining genetic risk and clinical outcomes in PLWH with HIV-related skin disorders. Protective alleles, such as DQA1*0501:0501, may contribute to immune regulation, offering potential targets for therapeutic interventions in PLWH with dermatoses. Our results highlight the importance of IL-1β and IFN-γ as key modulators in the progression of HIV infection and the development of HIV-related dermatoses. Further research is needed to explore the mechanisms underlying these associations, particularly in the Latvian population, to inform targeted therapeutic strategies. Full article