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关键词： Oncolytic Virus   Neoantigen Vaccines   Peptide-MHC Complexes   Tumor Immunotherapy  

摘要： Neoantigen vaccine is a promising breakthrough in tumor immunotherapy. However, the application of this highly personalized strategy in the treatment of solid tumors is hindered by several obstacles, including very costly and time-consuming preparation steps, uncertainty in prediction algorithms and tumor heterogeneity. Universalization of neoantigen vaccine is an ideal yet currently unattainable solution to such limitations. To overcome these limitations, we engineered oncolytic viruses co-expressing neoantigens and neoantigen-binding major histocompatibility complex (MHC) molecules to force ectopic delivery of peptide-MHC ligands to T cell receptors (TCRs), enabling specific targeting by neoantigen vaccine-primed host immunity. When integrated with neoantigen vaccination, the engineered viruses exhibited potent cytolytic activity in a variety of tumor models irrespective of the neoantigen expression profiles, eliciting robust systemic antitumor immunity to reject tumor rechallenge and inhibit abscopal tumor growth with a favorable safety profile. Thus, this study provides a powerful approach to enhance the universality and efficacy of neoantigen vaccines, meeting the urgent need for universal neoantigen vaccines in the clinic to facilitate the further development of tumor immunotherapy.

关键词： AhR/IL-22   黄芪甲苷   溃疡性结肠炎   肠道屏障  

摘要： 目的：研究黄芪甲苷 （Astragaloside IV，AS-IV）对溃疡性结肠炎（Ulcerative colitis，UC）小鼠肠道屏障功能的影响，并探讨其潜在机制。方法：使用3%葡聚糖硫酸钠（Dextran sulfate sodium，DSS）构建小鼠UC模型，建模成功后分为空白对照组、模型空白对照组、黄芪甲苷低、中、高剂量组（10 mg/kg、20 mg/kg、40 mg/kg），各组灌胃相应药物，每日1次，连续给药10d。Western blotting检测AhR/IL-22通路的蛋白表达水平；荧光原位杂交技术检测结肠组织切片DAPI染色情况；流式细胞术检测细胞凋亡水平；qRT-PCR检测AHR、CYP1A1、IL-22等mRNA表达水平。结果：AS-IV可能通过促进AhR/IL-22通路改善结肠炎小鼠的肠道炎症状态，降低了肠道通透性，并促进了结肠紧密连接结构的修复。AhR拮抗剂CH223191可部分阻断AS-IV的治疗效果，而AhR激动剂FICZ可改善结肠炎小鼠的症状和肠道屏障功能。进一步的体外机制研究发现，AS-IV处理显著提高了MNK-3细胞中AhR下游靶蛋白CYP1A1的表达水平（p<0.01），并通过促进AhR核转位显著增强IL-22的分泌（p<0.01）。重要的是，在AhR基因沉默的MNK-3细胞（shAhR-MNK3）中，AS-IV对CYP1A1表达和IL-22分泌的促进作用被显著抑制（p<0.05），表明AS-IV通过AhR依赖性机制调控IL-22的产生。结论 AS-IV通过ILC3中的AhR/IL-22通路改善肠上皮屏障，改善结肠炎，从而为UC提供潜在的治疗方法。

关键词： IL-27p28   single positive thymocyte   Th2 bias   IFN-gamma   autoimmune disease  

摘要： The newly generated CD4 single-positive (SP) T lymphocytes are featured by enhanced IL-4 but repressed IFN-gamma production. The mechanisms underlying this functional bias remain elusive. Previous studies have reported that CD4(+) T cells from mice harboring dendritic cell (DC)-specific deletion of IL-27p28 display an increased capacity of IFN-gamma production upon TCR stimulation. Here, we demonstrated that similarly altered functionality occurred in CD4SP thymocytes, recent thymic emigrants (RTEs), as well as naive T cells from either Cd11c-p28(f/f) mice or mice deficient in the alpha subunit of IL-27 receptor. Therefore, DC-derived IL-27p28-triggered, IL-27R alpha-mediated signal is critically involved in the establishment of functional bias against IFN-gamma production during their development in the thymus. Epigenetic analyses indicated reduced DNA methylation of the Ifng locus and increased trimethylation of H3K4 at both Ifng and Tbx21 loci in CD4SP thymocytes from Cd11c-p28(f/f) mice. Transcriptome profiling demonstrated that Il27p28 ablation resulted in the coordinated up-regulation of STAT1-activated genes. Concurrently, STAT1 was found to be constitutively activated. Moreover, we observed increased accumulation of STAT1 at the Ifng and Tbx21 loci and a strong correlation between STAT1 binding and H3K4me3 modification of these loci. Of note, Il27p28 deficiency exacerbated the autoimmune phenotype of Aire(-/-) mice. Collectively, this study reveals a novel mechanism underlying the functional bias of newly generated CD4(+) T cells and the potential relevance of such a bias in autoimmunity.

关键词： gamma delta T17 cells   ROR gamma t   17A   Bmi-1   senescence-associated pathological cardiac hypertrophy  

摘要： New immunosenescence targets for preventing senescence-associated pathological cardiac hypertrophy (SA-PCH) need to be explored. In the present study, with physiologically aged human and mouse samples, the IL-17A level increased with physiological aging, heart failure (HF), and SA-PCH and was negatively correlated with thymic Bmi-1 expression. Bmi-1f/fLckCre+ mice and Bmi-1f/flittermates were generated to determine whether Bmi-1 delayed T cell aging by maintaining thymic T cell development to prevent SA-PCH. As a result, Bmi-1 promoted thymic T cell development by upregulating Notch signaling and prevented DN1 T cells from differentiating into gamma delta T17 cells by downregulating gamma delta T17 cell differentiation signaling. Bmi-1 upregulated Notch signaling by inhibiting p53-mediated Ikzf1 transcription at the-1,863 to-1,849 Ikzf1 promoter region. Bmi-1-RING1B promoted ROR gamma t ubiquitination and degradation byproteas-ome to inhibit the production of IL-17A in gamma delta T17 cells. Bmi-1 also downregulated Rorc transcribed by c-Maf by trimethylating H3K27 at the-1,511 to-1,497 Rorc promoter region. Subsequently, the number of peripheral gamma delta T17 cells infiltrating the heart tissues was reduced, while alleviating IL-17A-dependent cardiac aging, hypertrophy, dysfunction, senescence-associated secretory phenotype (SASP), and macrophage-myofibroblast transition, ultimately improving SA-PCH. The ROR gamma t inhibitor SR1001 and IL-17A neutralizing antibody ixekizumab prevented thymic ROR gamma t-IL-17A-dependent SA-PCH. Furthermore, ROR gamma t bound to Bmi-1 through ARG237 and to RING1B through GLU235, which could be used as a therapeutic strategy for SA-PCH to construct binding peptides promoting Bmi-1-RING1B binding to ROR gamma t and degrading ROR gamma t for inhibiting gamma delta T17 cell differentiation and IL-17A production. Thus, thymic Bmi-1 prevented IL-17A-dependent SA-PCH by decreasing gamma delta T17 cell numbers.

关键词： Leishmania major   ILC   NK cell   ICER   IFNγ  

摘要： Innate lymphoid cells (ILCs) participate in different skin diseases. Cutaneous leishmaniasis evokes Th1/Tc1-dominated immunity, while in immune-compromised individuals, a Th2/Treg/Th17-immune response dominates. Only few prior studies investigated the role of ILC in leishmaniasis. We show that following physiologic low dose infection with Leishmania major , both lesional NK cell and ILC1 numbers strongly increase. In addition, early lesional IFNγ production derives from type I ILCs. Genetic ablation of both NK cells and ILC1 (NK/ILC1 Δ mice) led to reduced early IFNγ expression with increased pathology, higher parasite burdens and delayed recovery. Furthermore, expression of inducible cAMP early repressor (ICER) is important for disease outcome, as ICER -/- mice exhibited significantly larger lesions. Interestingly, mice that lack ICER specifically in NK cells and ILC1 phenocopied the worsened disease outcome of ICER -/- mice, while ICER deficiency in T cells or macrophages alone failed to do so. In line, ICER deficiency in NK cells/ILC1 resulted in higher lesional parasite burden with fewer IFNγ-positive ILC1 compared to control animals. Thus, our data shows that both NK cells and ILC1 contribute to early parasite control by releasing IFNγ. ICER expression by ILC1 promotes recruitment of IFNγ + ILC1 in Leishmania infections important for development of protection against this important pathogen.

关键词： Glucocorticoids-induced osteonecrosis of the femoral head   Calcified cartilage zone remodeling   IL-1 beta   Cartilage degeneration   Biomechanics  

摘要： Glucocorticoids-induced osteonecrosis of the femoral head (GONFH) is characterized by progressive cartilage degeneration, yet the role of calcified cartilage zone (CCZ) remodeling in this process remains poorly understood. This study investigated how the inflammatory microenvironment within necrotic subchondral bone drove CCZ remodeling and subsequent cartilage degeneration. Using osteochondral tissues from GONFH patients and interleukin-1 beta (IL-1 beta)-treated hypertrophic chondrocytes induced by ATDC5 cells, we combined histology, immunohistochemistry, scanning electron microscopy, energy dispersive spectrometer, transmission electron microscopy, nanoindentation testing, enzyme linked immunosorbent assay and fluorescent tracking to evaluate morphological, biomechanical, and molecular changes. Our findings revealed that CCZ of GONFH exhibited significant thinning, matrix decomposition, demineralization, diminished mechanical strength, and increased porosity. Spatial analysis demonstrated a strong correlation between CCZ remodeling and site-specific cartilage degeneration. Notably, IL-1 beta was overexpressed in necrotic subchondral bone and the site deep zones of cartilage. It potently enhanced catabolic activity in hypertrophic chondrocytes, promoting matrix metalloproteinase expression while impairing mineralization capacity. This study uncovers a novel pathological cascade in GONFH: necrotic subchondral bone-derived IL-1 beta drives CCZ remodeling via biomechanical and biological pathways, leading to cartilage degeneration independent of femoral head collapse. Our findings highlight IL-1 beta as a critical therapeutic target, providing a rationale for subchondral bone-targeted anti-inflammatory strategies to mitigate GONFH *** AbstractNecrotic subchondral bone expresses inflammatory cytokines, especially IL-1 beta, and triggers pathological remodeling of the calcified cartilage zone (CCZ). This remodeling manifests as reduced thickness, matr

摘要： Cutaneous T-cell Lymphoma (CTCL) is a multistage disease characterized by rapid dissemination of malignant T lymphocytes from skin lesions to visceral organs and bone marrow. The cytokine IL-9 and its receptor (IL-9R) are aberrantly overexpressed in CTCL lesions and function to enhance tumor cell survival. Here, we uncovered a critical new role for IL-9 as a potent inducer of migration of malignant T-cells. Stimulation of IL-9R-expressing T-cell lymphoma cells with IL-9 induced a pseudohypoxic cellular state by elevating downstream levels of the pro-migratory and oxygen-sensing transcription factor, hypoxia inducible factor (HIF)-1α. High-throughput quantitative proteomics analyses of pseudohypoxic malignant T-cells identified the actin-modulating protein, Cofilin-1, as a pro-migratory CTCL-intrinsic target downstream of IL-9-HIF-1α signaling. Consistently, multicolor immunofluorescence staining revealed marked co-expression of Cofilin-1 with HIF-1α in both IL-9-treated human lymphoma cell lines and in patient CTCL skin biopsies compared to normal controls. Genetic knockdown of IL-9R or HIF-1α in human T-cell lymphoma lines by RNA interference significantly reduced both HIF-1α and Cofilin-1 co-expression and reversed IL-9-induced migration. Finally, pharmacological antagonism of HIF-1α activity using the FDA-designated orphan drug, echinomycin, significantly abrogated IL-9-triggered migration of both malignant T-cell lines as well as patient-derived T-cell lymphoma cells from CTCL biospecimens. Implications: Our results uncover a CTCL-intrinsic IL-9-HIF-1α-Cofilin-1 axis as a critical promoter of malignant T-cell migration. They further identify HIF-1α and Cofilin-1 as promising therapeutic targets to mitigate IL-9-induced CTCL dissemination.

关键词： neuropathic pain   pro-inflammatory cytokine   TNF-alpha   nerve injury   immunotherapy  

摘要： TNF-alpha is a pro-inflammatory cytokine that plays a pivotal role in the regulation of immune responses. It is predominantly produced by activated macrophages, although other cell types, such as T lymphocytes and NK cells, also contribute to its secretion. TNF-alpha participates in various physiological processes, including cell proliferation and differentiation. Moreover, TNF-alpha has been implicated in the pathogenesis of numerous inflammatory and autoimmune disorders. Recent studies have highlighted the important role of TNF-alpha in neuropathic pain, a complex and frequently disabling condition caused by nerve injury or dysfunction. Increased TNF-alpha levels in the nervous system have been associated with the onset of neuropathic pain, contributing to neuronal sensitization and alterations in pain signaling pathways. This study supports the idea that TNF-alpha connects the immune system with the nervous system, thereby supporting our understanding of the neuroimmune interface of pain and bringing a potential treatment against neuropathic pain: targeting TNF-alpha. Anti-TNF-alpha antibody administration reduces pain behaviors and neuroinflammation in preclinical animal models. Simultaneously, clinical trials are evaluating the safety and efficacy of anti-TNF-alpha treatments, with preliminary results indicating promising outcomes in patients experiencing neuropathic pain. Here, targeting TNF-alpha goes beyond its conventional spectrum of inflammatory pathologies and initiates a new mechanism-based approach to defining neuropathic pain, thereby improving the quality of life of the individuals affected and bringing together an area of colossal unmet clinical need.

关键词： Acute myeloid leukemia   Myelodysplastic syndrome   Bexmarilimab   CLEVER-1   Stabilin-1   Immunotherapy  

摘要： Treatment of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) requires new therapy options, especially for patients uneligible for intense chemotherapy or with relapsed or refractory disease. CLEVER-1 is a myeloid checkpoint protein, which can be targeted with a therapeutic function blocking antibody, bexmarilimab. Bexmarilimab has shown clinical efficacy in different solid tumors. Here, we show preclinical data demonstrating expression of CLEVER-1 on immature malignant myeloid cells and their derivates in MDS and AML bone marrow samples and AML cell lines. Highest CLEVER-1 levels were observed in AML with monocytic differentiation. Ex vivo treatment of AML/MDS bone marrow samples with bexmarilimab led to an increase in antigen-presenting human leukocyte antigen DR isotype (HLA-DR) molecule expression. Combination of bexmarilimab with current standard-of-care (SoC) drugs, azacitidine and venetoclax, showed potential for HLA-DR induction and enhanced killing of leukemic cells, respectively. Our non-clinical findings support the feasibility of CLEVER-1 inhibition in AML/MDS to induce antigen presentating molecule expression and potentially, an anti-leukemic effect together with SoC. Therapeutic targeting of CLEVER-1 with bexmarilimab is currently undergoing clinical investigation in the BEXMAB trial (NCT05428969).