Purpose:To explore whether NDV and/or NDV-induced IFNs regulate programmed death-1 ligand (PD-L1) expression and modulate the balance between inhibitory and stimulatory immune signals. Materials and Methods:Human non-malignant (NB1RGB and HEK293) and tumor (A549 and U87MG) cell lines were used. Cells were either infected with Newcastle disease virus (NDV) LaSota strain or treated with interferons (IFNs). PD-L1 expression was analyzed by flow cytometry, Western blotting, and immunofluorescence. The relationship between PD-L1, as an immune inhibitor, and major histocompatibility complex class I polypeptide-related sequence A (MICA), as an immune activator, was evaluated using duplex chromogenic in situ hybridization. To investigate whether the NDV-induced shift in the PD-L1/MICA axis was sufficient to activate natural killer group 2 member D (NKG2D) receptor-possessing cells within peripheral blood mononuclear cells (PBMCs), IFN-γ production was measured in PBMCs following 24 hours of co-culture with tumor and normal cell lines previously infected with NDV or treated with IFN-λ. Results:NDV infection and IFN treatment resulted in a reduction of PD-L1 expressions in specific cell types. This decrease was accompanied by a concurrent increase in MICA expression, as demonstrated by in situ hybridization. The shift in balance between PD-L1 and MICA correlated with enhanced activation of NKG2D receptor-expressing immune cells, evidenced by increased IFN-γ secretion. Conclusion:These findings suggest that NDV may exert antitumor effects by modulating the balance between inhibitory checkpoint molecules and stimulatory ligands, specifically through downregulation of PD-L1 and upregulation of MICA. This mechanism highlights the potential of NDV to enhance cytotoxic immune responses and supports its further development as a novel strategy in cancer immunotherapy.
Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH) is a major subtype of secondary HLH and is increasingly recognized as a heterogeneous entity. However, the clinical differences between acute EBV-HLH (AEBV-HLH) and chronic active EBV infection-associated HLH (CAEBV-HLH) have not been systematically characterized. We conducted a scoping review of PubMed up to December 7, 2024, and identified 168 eligible articles involving 714 adult patients with EBV-HLH, including 584 with AEBV-HLH and 130 with CAEBV-HLH. Epidemiologic features, clinical manifestations, treatment patterns, and prognostic factors were summarized and compared between the two subgroups. Patients with AEBV-HLH showed more severe HLH-related abnormalities, including lower blood counts and higher ferritin, triglyceride, lactate dehydrogenase, and plasma EBV-DNA levels, whereas central nervous system involvement was more frequent in CAEBV-HLH. The median overall survival was significantly longer in CAEBV-HLH (8.9 months) than AEBV-HLH (2.4 months, P=0.005). In the overall cohort, ferritin >5000 μg/L, soluble CD25 >10000 U/mL, EBV-DNA >10000 copies/mL, and receiving hematopoietic stem cell transplantation (HSCT) were independently associated with better overall survival. In subgroup analyses, soluble CD25, EBV-DNA, and HSCT remained independent predictors in AEBV-HLH, whereas undergoing HSCT was the only independent prognostic factor in CAEBV-HLH. These findings support distinct clinical and prognostic characteristics between AEBV-HLH and CAEBV-HLH, especially in adults. AEBV-HLH is characterized by a more fulminant inflammatory presentation, whereas CAEBV-HLH more often follows a chronic course with greater extensive organ. HSCT appears to be central to long-term outcome in both subtypes.
Teridah Ernala Ginting,1– 3 Young Othiwi Larasati,1 Vina Cornelia,1 Nur Rahmaniah Hidayat,1 Salomo Christian,1 Kamaluddin Zarkasie,4 Irawan Yusuf1,51Division of Immunology, Mochtar Riady Institute for Nanotechnology, Universitas Pelita Harapan, Tangerang, Banten, Indonesia; 2Faculty of Medicine, Universitas Pelita Harapan, Tangerang, Banten, Indonesia; 3Global Health Department, Association of Public Health Laboratories, Bethesda, MD, USA; 4Faculty of Veterinary Medicine, PT. IPB Shigeta Animal Pharmaceuticals, Bogor Agricultural University, Bogor, West Java, Indonesia; 5Department of Physiology, Faculty of Medicine, Hasanuddin University, Makassar, South Sulawesi, IndonesiaCorrespondence: Teridah Ernala Ginting, Division of Immunology, Mochtar Riady Institute for Nanotechnology, Universitas Pelita Harapan, Tangerang, Banten, Indonesia; Faculty of Medicine, Universitas Pelita Harapan, Tangerang, Banten, Indonesia, Tel +62 21 5421 0123, Fax +62 21 5421 0110, Email tginting@mrinstitute.orgPurpose: To explore whether NDV and/or NDV-induced IFNs regulate programmed death-1 ligand (PD-L1) expression and modulate the balance between inhibitory and stimulatory immune signals.Materials and Methods: Human non-malignant (NB1RGB and HEK293) and tumor (A549 and U87MG) cell lines were used. Cells were either infected with Newcastle disease virus (NDV) LaSota strain or treated with interferons (IFNs). PD-L1 expression was analyzed by flow cytometry, Western blotting, and immunofluorescence. The relationship between PD-L1, as an immune inhibitor, and major histocompatibility complex class I polypeptide-related sequence A (MICA), as an immune activator, was evaluated using duplex chromogenic in situ hybridization. To investigate whether the NDV-induced shift in the PD-L1/MICA axis was sufficient to activate natural killer group 2 member D (NKG2D) receptor-possessing cells within peripheral blood mononuclear cells (PBMCs), IFN-γ production was measured in PBMCs following 24 hours of co-culture with tumor and normal cell lines previously infected with NDV or treated with IFN-λ.Results: NDV infection and IFN treatment resulted in a reduction of PD-L1 expressions in specific cell types. This decrease was accompanied by a concurrent increase in MICA expression, as demonstrated by in situ hybridization. The shift in balance between PD-L1 and MICA correlated with enhanced activation of NKG2D receptor-expressing immune cells, evidenced by increased IFN-γ secretion.Conclusion: These findings suggest that NDV may exert antitumor effects by modulating the balance between inhibitory checkpoint molecules and stimulatory ligands, specifically through downregulation of PD-L1 and upregulation of MICA. This mechanism highlights the potential of NDV to enhance cytotoxic immune responses and supports its further development as a novel strategy in cancer immunotherapy.Keywords: Newcastle disease virus, PD-L1, MICA, NKG2D, interferons, oncolytic virotherapy
Tiankuo Gao, Chun Yang, Yingxin Zhu, Junling Hu, Chen Gong, Yini Wang, Yue SongDepartment of Hematology, Capital Medical University Affiliated Beijing Anzhen Hospital, Beijing, 100029, People’s Republic of ChinaCorrespondence: Yini Wang; Yue Song, Email wangyini@ccmu.edu.cn; xueqifeng1992@163.comAbstract: Epstein–Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH) is a major subtype of secondary HLH and is increasingly recognized as a heterogeneous entity. However, the clinical differences between acute EBV-HLH (AEBV-HLH) and chronic active EBV infection-associated HLH (CAEBV-HLH) have not been systematically characterized. We conducted a scoping review of PubMed up to December 7, 2024, and identified 168 eligible articles involving 714 adult patients with EBV-HLH, including 584 with AEBV-HLH and 130 with CAEBV-HLH. Epidemiologic features, clinical manifestations, treatment patterns, and prognostic factors were summarized and compared between the two subgroups. Patients with AEBV-HLH showed more severe HLH-related abnormalities, including lower blood counts and higher ferritin, triglyceride, lactate dehydrogenase, and plasma EBV-DNA levels, whereas central nervous system involvement was more frequent in CAEBV-HLH. The median overall survival was significantly longer in CAEBV-HLH (8.9 months) than AEBV-HLH (2.4 months, P=0.005). In the overall cohort, ferritin > 5000 μg/L, soluble CD25 > 10000 U/mL, EBV-DNA > 10000 copies/mL, and receiving hematopoietic stem cell transplantation (HSCT) were independently associated with better overall survival. In subgroup analyses, soluble CD25, EBV-DNA, and HSCT remained independent predictors in AEBV-HLH, whereas undergoing HSCT was the only independent prognostic factor in CAEBV-HLH. These findings support distinct clinical and prognostic characteristics between AEBV-HLH and CAEBV-HLH, especially in adults. AEBV-HLH is characterized by a more fulminant inflammatory presentation, whereas CAEBV-HLH more often follows a chronic course with greater extensive organ. HSCT appears to be central to long-term outcome in both subtypes.Keywords: Epstein–Barr virus, hemophagocytic lymphohistiocytosis, scoping review
Background:Nivolumab is used as a second-line treatment for pleural mesothelioma (PM); however, predictive or prognostic biomarkers remain unclear. We aimed to identify factors associated with survival in nivolumab-treated PM patients. Methods:This retrospective, multi-institutional cohort study included patients with PM who received nivolumab monotherapy as a second-line or later treatment at 18 hospitals in Japan. We evaluated associations of progression-free survival (PFS) and overall survival (OS) with baseline clinical variables, protein expression in tumor tissue specimens obtained before first-line therapy by immunohistochemical (IHC), and tumor mutational and copy-number profiles detected by next-generation sequencing (NGS). Results:Fifty-five patients were enrolled, with evaluable IHC in 42 and NGS in 33. V-domain immunoglobulin suppressor of T-cell activation (VISTA) expression was classified as high or low using a cutoff of 10% VISTA-positive tumor cells. High VISTA expression (n=35) was significantly associated with improved PFS and OS compared with low expression (n=7) (PFS: median, 5.1 vs 2.4 months, p = 0.001; OS: median, 12.8 vs 4.3 months, p = 0.007). Multivariate analysis confirmed high VISTA expression as an independent predictor of prolonged PFS and OS (PFS: hazard ratio [HR] 0.14, p < 0.001; OS: HR 0.38, p = 0.044). Conclusion:Low tumor-cell VISTA expression was associated with poorer outcomes following nivolumab treatment; however, independent validation in prospective studies with a comparator arm is required before VISTA expression can be used to guide treatment selection. These findings support further investigation of biomarkers for combination strategies such as nivolumab-ipilimumab or chemoimmunotherapy in PM.
Mitura-Lesiuk M, Najda P, Rdzanek O, et al. Immunotargets Ther. 2026;15:603087. https://doi.org/10.2147/ITT.S603087 The following article has been removed from the Dove Medical Press journal, Immunotargets and Therapy: Mirua-Lesiuk M, Najda P, Rdzanek O, Bogucka J, Różycka K, Dubaj M, and Zawitkowska J, “Blinatumomab for Pediatric High-Risk B-Cell Precursor Acute Lymphoblastic Leukemia: Safety, MRD Response and Survival in a Single-Center Retrospective Cohort” (https://doi.org/10.2147/ITT.S603087). Published online: 24 April 2026 This article has been removed in accordance with journal editorial policies.
Introduction:Novel predictive biomarkers are needed to optimize immunotherapy-based treatment response in non-small cell lung carcinoma (NSCLC). T cell modulatory features may limit the ability of T cells to mount effective anti-tumor responses and could predict immune fitness and responsiveness to therapy. We investigated the prognostic and predictive value of CD8+ T cells with an exhausted phenotype, specifically those co-expressing Programmed Death 1 (PD-1) and T cell factor 1 (TCF-1), in peripheral blood of NSCLC patients before any systemic treatment. Methods:Two patient cohorts were analyzed: a) 32 patients with early and locally advanced disease (stage I-IIIA; cohort A) who did not receive immunotherapy, and b) 47 patients with advanced disease (stage IIIB-IV) who received chemo-immunotherapy. Multicolor flow cytometry was used to assess CD8+ T cell subpopulations co-expressing PD-1 and TCF-1. Results:PD-1+TCF1+ progenitor (early) exhausted T cells were found at high frequencies in all NSCLC patients compared with healthy donors, regardless of tumor stage. In cohort A, patients with high levels of CD3+CD8+PD-1+TCF1+ T cells had significantly improved DFS (p= 0.038), while those with high CD3+CD8+PD-1+TCF1- T cells had significantly worse DFS (p= 0.028). In cohort B, high levels of CD3+CD8+PD-1+TCF1+ T cells were associated with shorter PFS (p= 0.027). No association with OS was observed in cohort A. Conversely, in cohort B, high CD3+CD8+PD-1+TCF1+ T cell levels correlated with shorter OS (p= 0.045), while high CD3+CD8+PD-1+TCF1- T cell levels correlated with longer OS (p= 0.010). Conclusion:Therefore, here we show that circulating PD-1⁺TCF1+ T cells correlated differentially with treatment outcome in early and late NSCLC stage patients.
Background:Lung cancer is the leading cause of cancer mortality worldwide, and despite advances in surgery, chemotherapy, radiotherapy, and immunotherapy, challenges persist due to off-target toxicity and limited specificity. Photodynamic therapy (PDT), a minimally invasive treatment using photosensitizers and light to induce ROS-mediated cell death, has been explored for early-stage lung cancer; however, its clinical utility remains limited by poor tissue penetration, nonspecific photosensitizer uptake, and oxygen dependence. Discussion:Near-infrared photoimmunotherapy (NIR-PIT) is a highly specific cancer treatment that overcomes many limitations of conventional PDT. It employs antibody-photoabsorber conjugates, such as monoclonal antibodies linked to IRDye700DX, which bind selectively to cancer cell surface antigens and are activated by 690-nm NIR light. This illumination induces a unique, non-ROS-dependent cell death, "photochemosis", marked by immediate physical disruption of cancer cell membranes. Beyond direct cytotoxicity, NIR-PIT elicits robust immunogenic cell death, promotes systemic antitumor immunity, and permits repeated treatment cycles without compromising safety. The air-rich lung environment and deep penetration of NIR light make lung cancer an ideal NIR-PIT candidate. Advances in light-delivery devices-including endoscopic catheters, flexible LED systems, and endovascular therapy-based technologies-have greatly improved the feasibility of targeting deep pulmonary lesions for clinical implementation. Moreover, the modular design of NIR-PIT allows adaptation to diverse tumor targets, including EGFR and components of the tumor microenvironment, broadening its applicability. Conclusion:In this review, we provide a comprehensive overview of the mechanisms, advantages, and recent technological innovations of NIR-PIT, with a focus on its potential as a transformative therapeutic approach for lung cancer.
Background:Telitacicept is approved for acetylcholine receptor antibody-positive generalized myasthenia gravis (AChR-Ab+ gMG) in China. Although clinical trials have demonstrated its efficacy, real-world outcomes and safety require validation. This study compared telitacicept with conventional immunotherapy in a broader AChR-Ab+ GMG population, bridging the gap between RCT data and real-world practice. Methods:This retrospective real-world study (ChiCTR2500109279) included 215 patients with AChR-Ab+ gMG, with 43 receiving telitacicept and 172 undergoing conventional immunotherapy. Propensity score matching (1:1) yielded 35 patients per group. Treatment response was assessed by changes in Quantitative Myasthenia Gravis (QMG) and Myasthenia Gravis Activities of Daily Living (ADL) scores, time to minimal symptom expression (MSE), and prednisone use. Results:At week 4, the telitacicept group showed greater improvements than the control group in both QMG and ADL scores (QMG: 3.63±1.48 vs 0.37±2.76, p<0.001; ADL: 2.80±1.13 vs 0.46±2.44, p<0.001). These benefits were more pronounced at week 24 and sustained throughout follow-up (QMG: 10.30±4.19 vs 2.86±3.21, p<0.001; ADL: 8.06±3.37 vs 2.63±2.07, p<0.001). The telitacicept group also reached MSE earlier (median 5 months) and had more patients achieving MSE by week 24 (57.1% vs 11.4%, p<0.001), with lower cumulative prednisone doses over 24 weeks (2325 mg vs 6525 mg, p<0.001). A progressive decrease in IgM/IgG ratio was observed during treatment. Telitacicept was well-tolerated with no serious adverse events. Conclusion:This real-world study demonstrates that telitacicept effectively improves symptoms and maintains stability in AChR Ab+ gMG patients, with faster onset, reduced corticosteroid dependence, and favorable safety versus conventional immunotherapy.
Background:Anlotinib, a novel multi-target tyrosine kinase inhibitor, has demonstrated promising antitumor efficacy by inhibiting angiogenesis. However, the potential therapeutic benefits and underlying mechanisms of combining anlotinib with immune checkpoint inhibitors in colorectal cancer remain unclear. Methods:Syngeneic models of colorectal cancer were established and treated with anlotinib, PD-1/PD-L1-IN-9 hydrochloride, or their combination. Tumor tissues were analyzed using immunohistochemistry, and Western blotting to assess angiogenesis-associated markers, tissue hypoxia, and key molecular markers. Flow cytometry, ELISA, and immunostaining were performed to evaluate immune cell infiltration, cytokine expression, and the tumor immune microenvironment. Results:The combination of anlotinib and PD-1/PD-L1-IN-9 hydrochloride significantly inhibited tumor growth compared to monotherapy, associated with improved neovascularization and alleviated hypoxia. Combined therapy increased CD8+ T cell infiltration, reduced immunosuppressive cell populations, and partially modulated cytokine profiles, thereby enhancing the antitumor immune response. Conclusion:Anlotinib combined with PD-1/PD-L1-IN-9 hydrochloride exhibits superior antitumor efficacy in colorectal cancer compared to either agent alone, potentially by reshaping the tumor microenvironment. These findings support further exploration of combined anti-angiogenic and immune checkpoint therapy as a promising strategy for colorectal cancer treatment.
Multiple sclerosis (MS) is a chronic autoimmune disorder of CNS with demyelination, neurodegeneration and compartmentalized inflammatory disorder. Excessive T-helper cell (CD4+) activation and unregulated cytokine signaling play a key role in its onset and progression. These changes impair communication between peripheral immune cells and CNS resident microglia, astrocytes and oligodendrocytes. This review provides an overview on the contribution of specific subsets of T-helper cells to MS pathology/immunity. Th1 cells release interferon-γ and lymphotoxin, that stimulate activation of myeloid cells/antigen presentation. Activated by IL-23, the Th17 cells produce IL-17A/F that lowers the blood-brain barrier (BBB) integrity, recruit neutrophils and monocytes, and enhance microglial killing. Activation of CD4+ T cells leads to activation of B cells via T follicular helper cells which couple these processes through the production of IL-21 and CXCR5. This leads to the development of tissue-like aggregates and intrathecal antibody production. T-cell plasticity adds to epitope spreading as well as chronic inflammation, IL-22, IL-9, IL-1β, IL-6, and TGF-β (these are additional mediators involved in the regulation of effector phenotypes). In MS, the regulation of dendritic cell co-stimulation and of glial activation often does not work. This is due to the lack of control of dendritic-cells co-stimulation and the lack of regulation of glial activation by regulatory pathways such as FOXP3+ regulatory T cells and Tr1 cells that secrete IL-10 and TGF-Beta. The review also explores the cytokine network biomarkers, CSF and serum signatures and single-cell immune states, as well as existing and new drugs. These include migration blockade, targeting of S1P-receptors, anti-CD20 therapy, targeting of Th17/GM-CSF and JAK-STAT pathways, low-dose IL-2, approaches of targeting antigens and engineered Tregs. Investigating the areas of stage and compartment-specific CD4+ T-cell circuits can help to advance targeted immunomodulation in progressive MS and neuro-repair.
Background:Neuroblastoma (NBL) is the most common extracranial solid tumor in children, with a 50% survival rate in high-risk cases. Chemotherapy combination with immunotherapy is central to HR-NBL treatment. Aim:This study aimed to explore how Irinotecan influences the immune landscape of NBL cells, particularly focusing on the modulation of immune checkpoints relevant to future chemo-immunotherapy strategies. Methods:Two neuroblastoma cell lines, SK-N-BE(2) and SH-SY5Y, were exposed to sub-lethal doses of Irinotecan and IFN-γ. Flow cytometry assessed the expression of immune markers, including GD2, CD47, MHC I, and PD-L1. We also examined phagocytosis by macrophages and T-cell-mediated killing. In vivo studies using a neuroblastoma mouse model assessed the effects of Irinotecan and PBMC injections. Soluble CD47 was also measured in cell culture supernatants and exploratory patient plasma samples. Results:Treatment exposure was associated with modulation of several immune-related markers, including GD2, CD47, PD-L1, and MHC class I. While Irinotecan reduced macrophage-mediated phagocytosis, this effect was reversed by the addition of anti-CD47 antibodies. T-cell-mediated killing was enhanced when NBL cells were pre-treated with Irinotecan. In vivo studies showed that the combination of PBMCs and Irinotecan resulted in reduced tumor burden compared to either treatment alone. Furthermore, CD47 expression was detectable in-patient plasma, suggesting that soluble CD47 may warrant exploration in larger future cohorts. Conclusion:This pilot study suggests that irinotecan may modulate key immune checkpoints in neuroblastoma. These results supports further investigation of rational chemo-immunotherapy combinations, including GD2 and CD47-targeted combination strategies.
Introduction:Histamine dihydrochloride (HDC) has been shown to reduce metastatic spread of tumors by modulating myeloid cells, including immunosuppressive monocytes. Thrombospondin-1 (TSP-1), a matricellular glycoprotein present in the pre-metastatic niche, has also been implicated in limiting tumor metastasis. Microarray analyses have identified THBS1, encoding TSP-1, as an HDC-induced gene in human myeloid cells. This study investigated the mechanisms underlying HDC-induced TSP-1 expression and assessed whether TSP-1 contributes to the anti-metastatic effects of HDC in melanoma progression. Methods:TSP-1 expression and secretion were analyzed in human and murine myeloid cell subsets following HDC stimulation. Patient datasets were used to assess the clinical relevance of THBS1 expression in melanoma tissue. The functional significance of TSP-1 for HDC-mediated metastasis control was investigated in the B16F10 melanoma model of hematogenous lung metastasis in wild-type and TSP-1 knockout (KO) mice. Results:HDC robustly induced TSP-1 expression and secretion across multiple myeloid cell populations, including human and murine myeloid-derived suppressor cells. This effect was mediated via histamine type-2 receptors (H2Rs) and downstream cAMP-PKA signaling. Analysis of human melanoma datasets revealed reduced THBS1 expression in tumor tissue and an association between high THBS1 expression and improved overall survival. In addition, THBS1 expression correlated with the histamine synthesis gene histidine decarboxylase in human melanoma samples. In vivo, systemic HDC treatment increased lung TSP-1 levels and reduced pulmonary metastasis in wild-type but not in TSP-1 KO mice. Discussion:We identify TSP-1 as a downstream effector of HDC in myeloid cells and show that its induction is mediated by H2R-dependent cAMP-PKA signaling. The association between THBS1 expression and favorable survival in human melanoma supports a protective role for TSP-1. These findings suggest a previously unrecognized myeloid-cell mediated mechanism of HDC with potential relevance for metastasis control.
Background:Active generalised vitiligo (AGV) is an autoimmune disorder characterised by progressive melanocyte loss. However, the molecular mechanisms underlying AGV, particularly the roles of non-coding RNAs and their interaction with proteomic changes, remain poorly understood. The aim of this study was to systematically identify key regulatory networks and molecular changes in AGV by integrating proteomic and whole-transcriptome data. Methods:Data-independent acquisition mass spectrometry (DIA-MS) and whole transcriptome sequencing (WTS) were performed on whole blood samples from three AGV patients and three healthy individuals (HIs). Bioinformatic analyses were then used to identify differentially expressed proteins (DEPs), messenger RNAs (mRNAs), long non-coding RNAs (lncRNAs), circular RNAs (circRNAs) and microRNAs (miRNAs). Co-expression and competing endogenous RNA (ceRNA) networks were constructed and visualised using Cytoscape. Key hub genes and cytokine levels were then validated using quantitative reverse transcription PCR (qRT-PCR) and immunoassays in an independent cohort. Results:We identified 15 DEPs and 669 differentially expressed mRNAs (DEmRNAs), as well as significant alterations in 258 lncRNAs, 29 miRNAs and 44 circRNAs in AGV. Functional enrichment analysis revealed their involvement in chemokine signaling and lysosomal pathways. Protein-protein interaction network analysis revealed ten hub genes, including CXCL8, CXCR1, CXCR2 and IL1R2. We established a core ceRNA regulatory network featuring long non-coding RNAs (eg NUTM2B-AS1, LINC00894), circular RNAs (eg ASAP1, CDR2) and microRNAs (eg hsa-mir-3613-3p, hsa-mir-511-5p) that potentially modulate inflammatory responses. Experimental validation confirmed significantly elevated levels of the pro-inflammatory cytokines IL-8 and TNF-α in AGV patients, and qRT-PCR results for nine of the ten hub genes were consistent with the sequencing data. Conclusion:Our integrated multi-omics analysis uncovers a novel ceRNA network and highlights the significant upregulation of IL-8 and TNF-α in AGV. These findings provide new insights into the post-transcriptional regulatory mechanisms and inflammatory pathways driving AGV and offer potential therapeutic targets.
Background:Eosinophilic esophagitis (EoE) is a chronic, allergen-driven, type 2 immune-mediated disease of the esophagus defined by symptoms of esophageal dysfunction and eosinophil-predominant mucosal inflammation (≥15 eosinophils per high-power field), with a rising global prevalence now exceeding 1 in 1,000 individuals in Western countries. Its pathogenesis extends far beyond eosinophils, encompassing epithelial alarmin signaling (TSLP, IL-33, IL-18), ILC2 and Th2 immune activation, and a convergent effector network of eosinophils, mast cells, and fibroblasts that drives barrier disruption and progressive fibrostenotic remodeling. Purpose:This narrative review synthesizes current evidence on the multi-layered immunopathogenesis of EoE, the evolving conceptualization of disease remission, established and emerging therapeutic options, and precision medicine strategies incorporating phenotypic and molecular endotype classification. Key Findings:EoE shares a pathophysiologic continuum with other atopic diseases, underpinned by convergent type 2 immune mechanisms and epithelial barrier gene defects. A recently characterized ILC2-amphiregulin-EGFR axis directly drives structural esophageal remodeling independent of eosinophil recruitment, providing a mechanistic explanation for the histology-symptom dissociation that limits several biologic therapies. First-line therapies-proton pump inhibitors (PPIs), swallowed topical corticosteroids (STCs), and dietary elimination-achieve histologic remission in 45-90% of patients. Dupilumab, the first approved biologic, achieves histologic remission in approximately 59-60% of patients versus 5-6% with placebo at week 24. An expanding pipeline targets IL-13, IL-5R, TSLP, mast cells, and JAK-STAT pathways alongside optimized steroid formulations and oral small molecules. Conclusion:EoE is entering an era of precision therapeutics. Integrating molecular endotyping, multi-effector immunopathology, and multidimensional disease activity assessment will be essential to optimize long-term outcomes, prevent fibrostenotic progression, and individualize the expanding armamentarium of targeted therapies.
Background:B cell maturation antigen (BCMA)-targeted chimeric antigen receptor T cell (CAR-T) therapy has improved outcomes for relapsed/refractory multiple myeloma (R/R MM), but most patients eventually relapse, largely due to antigen escape, clonal heterogeneity, and immune-evasive tumor subclones. Novel targets are urgently needed to complement BCMA CAR-T and reduce relapse. Methods:We analyzed several single-cell transcriptomic datasets from patients who relapsed after BCMA CAR-T to identify relapse-associated surface antigens. We characterized ITGA8 expression in normal tissues and hematopoietic cells, evaluated its biological function in myeloma cells, and generated α8β1-targeted CAR-T cells. Preclinical efficacy was assessed in vitro and in xenograft models in combination with BCMA CAR-T. Results:ITGA8 was significantly enriched in MM cells at early relapse following BCMA CAR-T therapy, marking a quiescent, immune-evasive subpopulation. ITGA8 was absent from normal hematopoietic stem and immune cells but showed restricted expression in vascular smooth muscle cells. α8β1 CAR-T specifically lysed ITGA8-positive myeloma cells and complemented with BCMA CAR-T to control tumor in models mimicking antigen loss. Conclusion:This preclinical proof-of-concept study identifies integrin α8β1 as a potential CAR-T target worthy of further development for BCMA-resistant relapsed MM. While short-term tumor control was improved, this does not equate to validated clinical relapse prevention. Safety related to off-tumor expression in non-hematopoietic tissues remains to be fully evaluated.
Colorectal cancer (CRC) is a highly prevalent malignant tumor of the digestive tract worldwide, with significant regional variations in its epidemiological characteristics. Traditional treatments including surgery, chemotherapy, and radiotherapy have limited efficacy and substantial adverse events, which can no longer meet clinical needs. In recent years, immunotherapy has brought new breakthroughs for CRC by reshaping the tumor microenvironment (TME) and blocking tumor immune escape. This review systematically summarizes the core mechanisms and clinical applications of major immunotherapies such as immune checkpoint inhibitors (ICIs) and oncolytic viruses (OVs). We focus on individualized treatment selection for different molecular subtypes (pMMR/MSS vs. dMMR/MSI-H), biomarker screening, efficacy evaluation, drug resistance mechanisms, and countermeasures. We also discuss novel targets and biomarker optimization for precision therapy. In addition, given the unique immune-related adverse events, we introduce the CRC "SSEIE" nursing model and its value in whole-process management. This review integrates the latest advances in CRC immunotherapy and nursing interventions, providing a reference for optimizing clinical regimens, improving nursing quality, and enhancing patient prognosis.
Background:Grade 4 immune-related adverse events (irAEs) is life-threatening complications of immune checkpoint inhibitor therapy. Due to its rarity and scarcity of data, there is a lack of systematic research on key factors influencing poor prognosis. This exploratory study aimed to identify clinical features robustly associated with mortality in patients with grade 4 irAEs. Given the extremely small sample size and high‑dimensional data, a triangulation approach integrating traditional univariate statistics and machine learning to maximize the reliability of feature selection. Methods:This study included 26 cancer patients admitted to the ICU for grade 4 irAEs. To maximize robustness from limited data, a "triangulation" approach was employed. Prognostic features were independently identified through two parallel approaches: (1) traditional univariate statistical analysis, and (2) multiple machine learning algorithms evaluated by Leave-One-out Cross-Validation. Features consistently highlighted as significant by both independent methodologies were integrated to form a final high-confidence feature set. Results:Univariate analysis identified 21 features significantly associated with mortality. Machine learning analysis refined this to 11 important features. Through "triangulation", 8 features were consistently validated: body mass index and VEGF-inhibitors were inversely associated with mortality, while vasopressor therapy, oxygen therapy, lactate levels at day 1 and 2, pneumonia and percentage of neutrophils, exhibited a positive correlation with the mortality. Conclusion:This small-sample exploratory study identified 8 routinely available early ICU clinical features robustly associated with mortality in grade 4 irAEs patients using a "triangulation" framework. These characteristics highlight the pivotal roles of shock, respiratory failure, and inflammation. While not directly constructing a clinical prediction model, they may facilitate early risk stratification and provide hypotheses for prioritized validation in future large-sample studies.
Systemic mastocytosis (SM) is a rarely occurring clonal mast-cell disorder defined by aberrant mast-cell accumulation and episodic or chronic mediator release, giving rise to a broad range of manifestations from pruritus and flushing to gastrointestinal symptoms and anaphylaxis. In non-advanced SM, mediator-related symptoms are the major source of morbidity and substantially impair quality of life. Traditional symptom-directed therapies-including antihistamines, leukotriene modifiers, and mast-cell stabilizers-remain the foundation of care, but a subset of patients experience persistent, refractory symptoms. Advances in mast-cell biology have expanded therapeutic options for these patients, including selective KIT inhibitors, mast-cell--modulating small molecules, inhibitory-receptor agonists, epithelial-derived cytokine blockade, and agents targeting IgE-dependent and IgE-independent activation pathways. Key gaps remain, including the absence of validated biomarkers that distinguish activation from mast-cell burden, limited long-term safety data, and uncertainty around optimal dosing strategies. This review summarizes current understanding of mediator-driven disease in non-advanced SM and highlights targeted, mechanism-based therapies for refractory symptoms.
