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PubMed2026

Integrated pan-cancer profiling highlights OSR2 as a prognostic indicator and immune-associated biomarker.

BACKGROUND: Odd-skipped-related 2 (OSR2), encoded by the OSR2 gene, has been reported to function as a checkpoint associated with CD8⁺ T-cell exhaustion in the tumor microenvironment of solid malignancies, suggesting its potential as a therapeutic target to improve immunotherapeutic responses. Nevertheless, the molecular and clinical significance of OSR2 across diverse cancer types has not yet been systematically investigated, and its pan-cancer expression profile, prognostic implications, and associations with tumor immunity remain to be fully elucidated. METHODS: In this study, we integrated datasets from The Cancer Genome Atlas (TCGA), the Genotype-Tissue Expression (GTEx) portal, and the Human Protein Atlas to construct a systematic pan-cancer profile of OSR2. The prognostic value of OSR2 was comprehensively assessed using univariate Cox regression, survival analysis, and receiver operating characteristic (ROC) curve analysis. In addition, we performed an in-depth analysis of the relationships between OSR2 and multiple molecular and immunological features, including copy number variation (CNV), DNA methylation, tumor mutational burden (TMB), microsatellite instability (MSI), immune-related gene expression, immune cell infiltration, and drug sensitivity, with the aim of exploring its potential immunological associations with the tumor microenvironment. RESULTS: OSR2 expression was significantly upregulated or downregulated in the majority of tumor tissues relative to normal counterparts and exhibited distinct cancer-type-specific patterns across clinical stages. CNV alterations and aberrant DNA methylation were closely associated with abnormal OSR2 mRNA expression in multiple cancers. Prognostic analyses indicated that OSR2 expression was significantly associated with overall survival, disease-specific survival, disease-free interval, and progression-free interval across multiple cancer types, showing either risk-associated or protective associations in a tumor-context-dependent manner. Furthermore, OSR2 expression showed strong associations with immune cell infiltration, particularly T-cell subsets, and was significantly correlated with the expression of multiple immune checkpoint-related genes across diverse malignancies. OSR2 expression was also closely associated with TMB, MSI, and sensitivity to multiple anticancer agents. CONCLUSION: Taken together, these findings suggest that OSR2 is associated with prognosis and immune-related features across multiple cancer types. OSR2 may be linked to features of the tumor immune microenvironment through its relationships with immune cell infiltration, immune checkpoint gene expression, and genomic instability, and thus may serve as a candidate biomarker for further investigation in cancer immunotherapy.

CD8⁺ T-cell↗

PubMed2006

Checkpoint blockade in cancer immunotherapy.

The progression of a productive immune response requires that a number of immunological checkpoints be passed. Passage may require the presence of excitatory costimulatory signals or the avoidance of negative or coinhibitory signals, which act to dampen or terminate immune activity. The immunoglobulin superfamily occupies a central importance in this coordination of immune responses, and the CD28/cytotoxic T-lymphocyte antigen-4 (CTLA-4):B7.1/B7.2 receptor/ligand grouping represents the archetypal example of these immune regulators. In part the role of these checkpoints is to guard against the possibility of unwanted and harmful self-directed activities. While this is a necessary function, aiding in the prevention of autoimmunity, it may act as a barrier to successful immunotherapies aimed at targeting malignant self-cells that largely display the same array of surface molecules as the cells from which they derive. Therapies aimed at overcoming these mechanisms of peripheral tolerance, in particular by blocking the inhibitory checkpoints, offer the potential to generate antitumor activity, either as monotherapies or in synergism with other therapies that directly or indirectly enhance presentation of tumor epitopes to the immune system. Such immunological molecular adjuvants are showing promise in early clinical trials. This review focuses on the results of the archetypal example of checkpoint blockade, anti-CTLA-4, in preclinical tumor models and clinical trials, while also highlighting other possible targets for immunological checkpoint blockade.

Animals↗

PubMed2006

Effective cancer therapy through immunomodulation.

MAbs directed toward tumor cells, tumor neovasculature, and host negative immunoregulatory elements (checkpoints) have emerged as useful immunotherapeutic agents against cancer. However, effective active modulation of the immune response with anticancer vaccines will require identifying appropriate tumor-rejection antigens; optimizing the interactions of peptides, antigen-presenting cells, and T cells; and blockading negative immunological checkpoints that impede an effective immune response. Checkpoints being targeted include CTLA-4 and PD1 that are negative signaling receptors expressed on activated T cells, CD4+CD25+ Foxp3-expressing Tregs (suppressor T cells), IL-2-mediated activation-induced cell death (AICD), and the cytokine TGFbeta.

Antibodies, Monoclonal↗

PubMed2026

Increased IL4I1 expression predicts poor survival and modulates the immune microenvironment in acute myeloid leukemia.

BACKGROUND: The immunometabolic enzyme Interleukin-4-induced-1 (IL4I1) is implicated in cancer pathogenesis, yet its specific function and clinical relevance in acute myeloid leukemia (AML) remain unclear. METHODS: Comparative analysis of IL4I1 mRNA levels between AML patients and normal controls was performed using the Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases. The Kaplan–Meier survival analysis was conducted to evaluate the prognostic value of IL4I1. Functional insights were derived from analyses of differentially expressed genes (DEGs), Gene Set Enrichment Analysis (GSEA), and Gene Ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment. Immune infiltration was evaluated using the ssGSEA, ESTIMATE, quanTIseq and single-cell RNA sequencing (scRNA-seq) analysis. Finally, in vitro and in vivo functional experiments were perfromed to explore the impact of IL4I1 on AML progression and immunoregulation. RESULTS: IL4I1 expression was significantly elevated in AML compared to normal controls (p = 0.0004) and associated with poorer overall survival (p = 0.003). Bioinformatic analysis revealed that IL4I1 was linked to immune-related pathways—including humoral immune response, leukocyte interactions, and chemokine signaling—and to cellular amino acid metabolism. Its expression correlated with immune cell infiltration and checkpoint molecule expression. Experimentally, IL4I1 promoted leukemia cell proliferation in vitro and in vivo (p < 0.05). Furthermore, silencing IL4I1 suppressed M2 macrophage polarization and reduced secretion of inflammatory factors (p < 0.05). CONCLUSIONS: IL4I1 may serve as a potential biomarker for poor prognosis and an attractive target for immune-based therapeutic interventions in AML.

Humans↗

PubMed1996

V(D)J recombination activates a p53-dependent DNA damage checkpoint in scid lymphocyte precursors.

Double-stranded DNA breaks (DSBs) trigger p53-mediated cell cycle arrest or apoptosis pathways that limit the oncogenic consequences of exposure to genotoxic agents, but p53-mediated responses to DSB generated by normal physiologic events have not been documented. "Broken" V(D)J coding ends accumulate in scid lymphocyte precursors as a consequence of a mutation in DNA-dependent protein kinase (DNA-PK). The ensuing failure to rearrange efficiently antigen receptors arrests lymphoid development. Here we show that scid thymocytes express high levels of p53 protein, attributable to recombinase activating gene (RAG)-dependent generation of DSB adjacent to V, D, and J gene segments. To examine the functional importance of p53 expression in vivo, we bred p53-/- scid mice. The absence of p53 facilitated production of in-frame V(D)Jbeta coding joints and developmental progression of scid thymocytes, in addition to a dramatic accumulation of pro-B cells. All mice developed disseminated pro-B or immature T cell lymphoma/leukemia by 7-12 weeks of age. We present evidence that p53 deficiency prolongs the survival of scid lymphocyte precursors harboring broken V(D)J coding ends, allowing the accumulation of aneuploid cells. These results demonstrate that a p53-mediated DNA damage checkpoint contributes to the immune deficiency characteristic of the scid mutation and limits the oncogenic potential of DSBs generated during V(D)J recombination.

Animals↗

PubMed2006

Burying the dead: the impact of failed apoptotic cell removal (efferocytosis) on chronic inflammatory lung disease.

Apoptosis and the removal of apoptotic cells (termed efferocytosis) are tightly coupled with the regulation of normal lung structure, both in the developing and adult organism. Processes that disrupt or uncouple this balance have the potential to alter normal cell turnover, ultimately resulting in the induction of lung pathology and disease. Apoptotic cells are increased in several chronic inflammatory lung diseases, including cystic fibrosis (CF), non-CF bronchiectasis, COPD, and asthma. While this may well be due to the enhanced induction of apoptosis, increasing data suggest that the clearance of dying cells is also impaired. Because efferocytosis appears to be a key regulatory checkpoint for the innate immune system, the adaptive immune system, and cell proliferation, the failure of this highly conserved process may contribute to disease pathogenesis by impeding both the resolution of inflammation and the maintenance of alveolar integrity. The recognition of impaired efferocytosis as a contributor to chronic inflammation may ultimately direct us toward the identification of new disease biomarkers, as well as novel therapeutic approaches.

Apoptosis↗

PubMed2026

Pan-cancer characterization of HMGA1 reveals its oncogenic role in tumor microenvironment and stemness: functional validation in pancreatic cancer migration and invasion.

BACKGROUND: HMGA1 is a chromatin-associated oncogenic factor implicated in tumor progression, epithelial-mesenchymal transition (EMT), stemness, and metastasis. However, its pan-cancer expression and prognostic patterns, epigenetic activation, and relationship with malignant-cell stemness/plasticity and tumor microenvironment (TME) remodeling in pancreatic adenocarcinoma (PAAD) remain incompletely defined. This study aimed to systematically characterize HMGA1 across cancers and clarify its clinical and biological relevance in PAAD. METHODS: Pan-cancer transcriptomic, clinical, genetic, methylation, immune, and stemness data were integrated from multiple public databases. PAAD single-cell RNA sequencing data were analyzed to localize HMGA1 expression, infer malignant-cell pseudotime, calculate a stemness module score, and assess ligand-receptor communication using CellChat. Public HMGA1-knockdown RNA sequencing data were reanalyzed to evaluate transcriptional remodeling. The Cancer Genome Atlas (TCGA)-PAAD expression and methylation data were used to assess TME-remodeling, immune-suppression, stemness/plasticity, cytokine/chemokine, checkpoint, and promoter-methylation features. HMGA1 expression and function were further examined using immunohistochemistry (IHC), quantitative real-time polymerase chain reaction, Western blotting, wound-healing assays, and Transwell migration and invasion assays. RESULTS: HMGA1 was upregulated in most tumor types, and high expression was associated with unfavorable survival in multiple cancers, including PAAD. In PAAD, HMGA1 was enriched in malignant epithelial cells and positively correlated with pseudotime (Spearman's rho =0.594), while the stemness module score increased along pseudotime (rho =0.748). HMGA1-high malignant cells showed markedly stronger CellChat-inferred outgoing communication, predominantly involving extracellular matrix (ECM)-receptor, adhesion-related, and selected immunomodulatory ligand-receptor axes. HMGA1 knockdown was associated with broad remodeling of EMT, TGF-β, Hedgehog, IL6/JAK/STAT3, KRAS, and cancer stem cell/stemness-related programs rather than uniform suppression of these programs. HMGA1 promoter methylation was inversely correlated with HMGA1 expression (rho =-0.633) and the TME-remodeling score (rho =-0.347). HMGA1 was associated with selected mediators, including PPIA, PLAU, ANXA1, LGALS9, TGFB1, CD276, and CD47, but not with a generalized checkpoint-high phenotype. Functionally, HMGA1 knockdown significantly reduced pancreatic cancer (PC) cell migration and invasion. CONCLUSIONS: These findings support an association-based model in which promoter hypomethylation-associated HMGA1 activation is linked to malignant epithelial stemness/plasticity, ECM/adhesion-dominant TME remodeling, selected immunomodulatory programs, and aggressive PAAD phenotypes. Further mechanistic and clinical validation is required before HMGA1 can be used for therapeutic stratification or immunotherapy-response prediction.

HMGA1↗

PubMed2004

Artemis sheds new light on V(D)J recombination.

V(D)J recombination represents one of the three mechanisms that contribute to the diversity of the immune repertoire of B lymphocytes and T lymphocytes. It also constitutes a major checkpoint during the development of the immune system. Indeed, any V(D)J recombination deficiency leads to a block of B-cell and T-cell maturation in humans and animal models, leading to severe combined immunodeficiency (T-B-SCID). Nine factors have been identified so far to participate in V(D)J recombination. The discovery of Artemis, mutated in a subset of T-B-SCID, provided some new information regarding one of the missing V(D)J recombinase activities: hairpin opening at coding ends prior to DNA repair of the recombination activating genes 1/2-generated DNA double-strand break. New conditions of immune deficiency in humans are now under investigations and should lead to the identification of additional V(D)J recombination/DNA repair factors.

DNA Repair↗

PubMed2004

Immune therapy for autoimmune diseases.

Our increasing understanding of the pathophysiology of autoimmune disease has revealed a number of checkpoints that can be targeted with immune therapy, including key mediators of lymphocyte adhesion and migration, destructive cytokines involved in tissue damage, and the complex of molecules critical in the presentation of self-antigen and the activation of autoaggressive T lymphocytes. In many organ-specific autoimmune diseases, the identity of the molecules attacked by T cells and autoantibodies is known and attempts are under way to tolerize the immune system with a high level of specificity to these targets.

Animals↗

PubMed2026

Convergent evolution of immune evasion in ESKAPE pathogens: A cross-pathogen architecture of conserved host-defense checkpoints.

Antimicrobial resistance in ESKAPE pathogens is primarily attributed to resistance genes, yet persistent infections despite appropriate therapy implicate immune evasion as an independent driver of treatment failure. Although immune-evasion mechanisms have been extensively characterized in individual pathogens, their shared architecture across the ESKAPE group remains insufficiently integrated. This review synthesizes current evidence to show that phylogenetically diverse ESKAPE pathogens have convergently evolved conserved strategies to evade host immunity under comparable selective pressures. A cross-pathogen immune-evasion framework emerges, encompassing impaired pathogen recognition, complement inhibition, phagocyte dysfunction, immunometabolic reprogramming, biofilm-mediated protection, and persistence-promoting inflammation, together with pathogen-specific virulence mechanisms. These processes intersect with adaptive immune dysfunction and emerging concepts, including quorum-sensing-mediated immunomodulation, trained immunity, and the itaconate-succinate immunometabolic axis, forming an interconnected persistence network rather than isolated virulence traits. This systems-level perspective identifies conserved host-directed therapeutic targets that may complement conventional antimicrobial therapy across species. However, host-directed therapies, immunotherapeutics, and vaccines remain largely preclinical or have shown inconsistent clinical efficacy. Mechanistic evidence is strongest for Staphylococcus aureus, Pseudomonas aeruginosa, and Klebsiella pneumoniae, whereas substantial knowledge gaps persist for Enterococcus faecium, Acinetobacter baumannii, and Enterobacter spp. Overcoming persistent ESKAPE infections will require targeting conserved host-pathogen interactions alongside pathogen-specific antimicrobial resistance mechanisms.

Convergent immune evasion↗

PubMed2002

V(D)J recombination and DNA repair: lessons from human immune deficiencies and other animal models.

PURPOSE OF REVIEW: V(D)J recombination not only represents the main mechanism for the diversification of the immune system, it also constitutes a critical checkpoint in the development of both B and T lymphocytes. While a defect in V(D)J recombination leads to severe combined immune deficiency, a deregulation of this process can participate in the onset of lymphoid malignancies. RECENT FINDINGS: The careful analysis of human severe combined immune deficiency patients as well as engineered murine models provided several new interesting insights into the physiopathology of the V(D)J recombination process. A new factor of the V(D)J recombination/DNA repair machinery, Artemis, was identified based on its deficiency in human severe combined immune deficiency patients. It also became evident from knockout mouse studies that DNA repair factors that participate in V(D)J recombination can be considered as genomic caretakers. SUMMARY: While V(D)J recombination was first recognized as a critical checkpoint in the development of the immune system, the discovery of several DNA repair factors that participate in this reaction shed light on more general aspects of genomic stability and cancer predisposition.

Animals↗

PubMed2001

Disease resistant, NOD-related strains reveal checkpoints of immunoregulation in the pancreas.

The autoimmune diabetic NOD mouse serves as a model for human type 1 diabetes. Disease development is due to islet beta cell destruction in the context of immune cell infiltration of islets and inflammatory changes throughout the pancreas. In the present study we tried to identify immune reactivity patterns in the pancreas associated with diabetes resistance in NOD-related mouse strains. The pancreata of diabetes-prone female NOD/LtJ, NOD/Bom and of genetically related but diabetes-resistant strains; NOR, NON, NON.NOD-H2g7, NOD.NON-H-2nbl were obtained at the age of 70 days for semiquantitative analysis of insulitis and of mRNA expression by reverse transcriptase PCR. In addition, the response to a single dose of cyclophosphamide for synchronizing and accelerating the progression of insulitis was determined. The progression of insulitis and immune gene expression in response to cyclophosphamide revealed characteristic differences between the six strains. NOD/LtJ and NOD/Bom mice were found significantly to upregulate pancreatic IL-12p40 and IL-18 expression after cyclophosphamide treatment, followed by an increase in IFN-gamma mRNA levels. In contrast, the two MHC-haplotype H-2nbl expressing strains either up-regulated neither IL-12/IL-18 nor IFN-gamma gene expression. The two strains sharing MHC haplotype H-2g7 expression with NOD did respond to cyclophosphamide with IL-12p40/IL-18 gene expression. However, NON.NOD-H-2g7 mice failed to progress to IFN-gamma gene expression. NOR mice progressed to IFN-gamma expression but exhibited sustained IL-4 gene expression. Only severe intra-insulitis was associated with the expression of inducible NO synthase. The comparison of diabetes-prone and diabetes-resistant strains revealed three checkpoints of immune regulation in the pancreas. The earliest checkpoint is the induction of an IL-12p40/IL-18 response in innate immune or antigen-presenting cells. The next level of control is at the induction of IFN-gamma gene expression, and a third checkpoint is the maintenance or loss of antagonistic Th2 type reactions.

Animals↗

PubMed2002

Further checkpoints in Th1 development.

Tight control of Th1 immunity is essential to prevent immunopathology. Central to control of the IFN-gamma gene is the transcription factor T-bet, whose induction is Stat-1 dependent. IL-12 is dominant in directing Th1 development, while synergizing with IL-18 for IFNgamma production from differentiated Th1 cells. In this issue of Immunity, IL-27 is described, which acts in synergy with IL-12 early in Th1 development from naive T cells via the receptor TCCR/WSX-1. We review the coordination of these checkpoints in Th1 development and function.

Glycoproteins↗

PubMed2005

Activating and inhibitory IgG Fc receptors on human DCs mediate opposing functions.

Human monocyte-derived DCs (moDCs) and circulating conventional DCs coexpress activating (CD32a) and inhibitory (CD32b) isoforms of IgG Fcgamma receptor (FcgammaR) II (CD32). The balance between these divergent receptors establishes a threshold of DC activation and enables immune complexes to mediate opposing effects on DC maturation and function. IFN-gamma most potently favors CD32a expression on immature DCs, whereas soluble antiinflammatory concentrations of monomeric IgG have the opposite effect. Ligation of CD32a leads to DC maturation, increased stimulation of allogeneic T cells, and enhanced secretion of inflammatory cytokines, with the exception of IL-12p70. Coligation of CD32b limits activation through CD32a and hence reduces the immunogenicity of moDCs even for a strong stimulus like alloantigen. Targeting CD32b alone does not mature or activate DCs but rather maintains an immature state. Coexpression of activating and inhibitory FcgammaRs by DCs reveals a homeostatic checkpoint for inducing tolerance or immunity by immune complexes. These findings have important implications for understanding the pathophysiology of immune complex diseases and for optimizing the efficacy of therapeutic mAbs. The data also suggest novel strategies for targeting antigens to the activating or inhibitory FcgammaRs on human DCs to generate either antigen-specific immunity or tolerance.

Antigen-Antibody Complex↗

PubMed2026

RADX protects against intestinal inflammation by restraining IFI16-mediated innate immunity.

Genomic instability is increased in patients with inflammatory bowel disease (IBD), yet whether it contributes directly to disease pathogenesis remains unclear. Here, we identify RADX, a structural antagonist to RAD51 and a key regulator of replication fork stability, as a critical suppressor of intestinal inflammation by limiting innate immune sensing of replication-associated DNA damage. RADX deficiency exacerbates experimental colitis, with macrophages serving as the principal mediators of this phenotype. Mechanistically, RADX competes with the DNA sensor IFI16 for binding to single-stranded DNA (ssDNA). Loss of RADX promotes ssDNA accumulation, triggering IFI16-dependent activation of NF-κB signaling and inflammasome assembly, thereby driving intestinal inflammation. Consistent with these findings, two RADX variants identified in patients with IBD associate with reduced RADX protein expression, increased DNA damage signaling, and elevated IL-1β levels. Pharmacological inhibition of RAD51 with RI-1 alleviated colitis in both wild-type and Radx-deficient mice. Together, these findings establish a mechanistic link between genome instability and intestinal inflammation, identify a RADX-IFI16 checkpoint that restrains pathogenic innate immune activation, and nominate modulation of replication stress as a therapeutic strategy for IBD.

Animals↗

PubMed2006

Development of antibodies and chimeric molecules for cancer immunotherapy.

Monoclonal antibodies are among the most rapidly expanding class of therapeutics for cancer treatment. Monoclonal antibodies targeting non-Hodgkin's lymphoma (NHL), Her-2/neu highly expressing metastatic breast cancer, colorectal cancer, acute myelogenous leukemia, and B-cell chronic lymphocytic leukemia (CLL) have received FDA approval. Promising new targets for antibody therapy include cellular growth factor receptors, mediators of tumor-driven neo-angiogenesis, as well as host negative immunoregulatory checkpoints that impede an effective immune response to neoplasia. Antibody efficacy has been increased by genetic engineering to humanize the antibodies and to increase their effector functions including antibody dependent cellular cytotoxicity. Furthermore, antibodies have been armed with cytokines, chemotherapeutic agents, toxins, and radionuclides to augment their efficacy as tumor cytotoxic agents. As a consequence of these advances, 30 years after their first development, monoclonal antibodies have become an important standard approach for the therapy of neoplasia with 19 therapeutic monoclonal antibodies now approved by the FDA including 8 for the treatment of cancer.

Animals↗

PubMed2000

Functional dissection of BCR signaling pathways.

Signal transduction by the BCR is critical for progression through developmental checkpoints as well as for immune responses. Recent results obtained in mice deficient either in an adaptor molecule, BLNK (alternatively named SLP-65 or BASH), or in phosphatidylinositol 3-kinase have revealed similar - though not identical - phenotypes to those of Btk(-/-) mice, suggesting a functional link between BLNK, Btk and phosphatidylinositol 3-kinase.

Adaptor Proteins, Signal Transducing↗

PubMed2025

Liver cancer-specific prognostic model developed using endoplasmic reticulum stress-related LncRNAs and LINC01011 as a potential therapeutic target.

Liver cancer is a serious malignancy worldwide, and long noncoding RNAs (lncRNAs) have been implicated in its prognosis.It remains unclear how lncRNAs related to endoplasmic reticulum stress (ERS) influence liver cancer prognosis. Here, we analyzed RNA and clinical data from the Cancer Genome Atlas and sourced ERS-related genes from the Molecular Signatures Database. Co-expression analysis identified ERS-related lncRNAs, and Cox regression analysis as well as least absolute shrinkage and selection operator regression highlighted three lncRNAs for a prognostic model. Based on median risk scores, we classified patients into two risk groups. The high-risk group displayed poor prognosis, and this finding was validated in the test set. According to consistency clustering, the patients were assigned to two clusters, and tumor microenvironment scores were computed. Patients with a high mutation burden had worse outcomes. Furthermore, immune infiltration analysis indicated more immune cells and mutations in checkpoint molecules among high-risk individuals. Drug sensitivity varied between the risk groups. LINC01011 was selected for functional assays. Colony formation assay and CCK-8 assay revealed that silencing LINC01011 suppressed liver cancer cell proliferation. Transwell and scratch assays indicated that silencing LINC01011 inhibited liver cancer cell migration. Western blotting assay revealed that inhibiting LINC01011 induced apoptosis and simultaneously inhibited epithelial-mesenchymal transition. These findings confirm the validity of the prognostic model and indicate that LINC01011 could serve as a potential research target.

Humans↗