技术资料

SummaryMesenchymal stromal cells (MSCs) have been modified via genetic or pharmacological engineering into potent antigen-presenting cells-like capable of priming responding CD8 T cells. In this study,our screening of a variant library of Accum molecule revealed a molecule (A1) capable of eliciting antigen cross-presentation properties in MSCs. A1-reprogrammed MSCs (ARM) exhibited improved soluble antigen uptake and processing. Our comprehensive analysis,encompassing cross-presentation assays and molecular profiling,among other cellular investigations,elucidated A1’s impact on endosomal escape,reactive oxygen species production,and cytokine secretion. By evaluating ARM-based cellular vaccine in mouse models of lymphoma and melanoma,we observe significant therapeutic potency,particularly in allogeneic setting and in combination with anti-PD-1 immune checkpoint inhibitor. Overall,this study introduces a strong target for developing an antigen-adaptable vaccination platform,capable of synergizing with immune checkpoint blockers to trigger tumor regression,supporting further investigation of ARMs as an effective and versatile anti-cancer vaccine. Graphical abstract Highlights•Treatment with A1/antigen mix reprograms MSCs into antigen-presenting cells•The antigen cross-presenting ability of ARM cells require ROS and UPR•ARMs synergize with immune-checkpoint inhibitors in priming potent antitumoral activity Classification Description: Immunology; Pharmaceutical engineering; Cancer View Publication

Interferon gamma (IFNγ) is a critical cytokine known for its diverse roles in immune regulation,inflammation,and tumor surveillance. However,while IFNγ levels were elevated in sera of most newly diagnosed acute myeloid leukemia (AML) patients,its complex interplay in AML remains insufficiently understood. We aim to characterize these complex interactions through comprehensive bulk and single-cell approaches in bone marrow of newly diagnosed AML patients. We identify monocytic AML as having a unique microenvironment characterized by IFNγ producing T and NK cells,high IFNγ signaling,and immunosuppressive features. IFNγ signaling score strongly correlates with venetoclax resistance in primary AML patient cells. Additionally,IFNγ treatment of primary AML patient cells increased venetoclax resistance. Lastly,a parsimonious 47-gene IFNγ score demonstrates robust prognostic value. In summary,our findings suggest that inhibiting IFNγ is a potential treatment strategy to overcoming venetoclax resistance and immune evasion in AML patients. IFNγ signaling is important in the pathogenesis and immune response,emphasizing the need for investigation of its role. Here,the authors show that IFNγ plays a key role in shaping immune microenvironment in AML and developing resistance,providing insights for potential therapeutic strategies. View Publication

SummaryADG106,a ligand-blocking agonistic antibody targeting CD137 (4-1BB),exhibits promising results in preclinical studies,demonstrating tumor suppression in various animal models and showing a balanced profile between safety and efficacy. This phase 1 study enrolls 62 patients with advanced malignancies,revealing favorable tolerability up to the 5.0 mg/kg dose level. Dose-limiting toxicity occurs in only one patient (6.3%) at 10.0 mg/kg,resulting in grade 4 neutropenia. The most frequent treatment-related adverse events include leukopenia (22.6%),neutropenia (22.6%),elevated alanine aminotransferase (22.6%),rash (21.0%),itching (17.7%),and elevated aspartate aminotransferase (17.7%). The overall disease control rates are 47.1% for advanced solid tumors and 54.5% for non-Hodgkin’s lymphoma. Circulating biomarkers suggest target engagement by ADG106 and immune modulation of circulating T,B,and natural killer cells and cytokines interferon γ and interleukin-6,which may affect the probability of clinical efficacy. ADG106 has a manageable safety profile and preliminary anti-tumor efficacy in patients with advanced cancers (this study was registered at ClinicalTrials.gov: NCT03802955). Graphical abstract Highlights•ADG106 is a ligand-blocking agonistic antibody targeting CD137•ADG106 enhances cytotoxic T cell activity within the tumor environment•ADG106 shows manageable safety and preliminary anti-tumor efficacy in this phase 1 study Ma et al. demonstrate the safety,efficacy,and survival benefits of ADG106,a fully human agonistic monoclonal IgG4 antibody targeting a unique and crossreactive epitope of CD137,in patients with advanced solid tumors and non-Hodgkin’s lymphoma. They show that ADG106 exhibits a favorable safety profile and encourages anti-tumor activity. View Publication

Peripheral T cell lymphomas are typically aggressive with a poor prognosis. Unlike other hematologic malignancies,the lack of target antigens to discriminate healthy from malignant cells limits the efficacy of immunotherapeutic approaches. The T cell receptor expresses one of two highly homologous chains [T cell receptor β-chain constant (TRBC) domains 1 and 2] in a mutually exclusive manner,making it a promising target. Here we demonstrate specificity redirection by rational design using structure-guided computational biology to generate a TRBC2-specific antibody (KFN),complementing the antibody previously described by our laboratory with unique TRBC1 specificity (Jovi-1) in targeting broader spectrum of T cell malignancies clonally expressing either of the two chains. This permits generation of paired reagents (chimeric antigen receptor-T cells) specific for TRBC1 and TRBC2,with preclinical evidence to support their efficacy in T cell malignancies. The T cell receptor β-chain is expressed in two isoforms,TRBC1 and TRBC2,with clonally expanded mature T cell lymphomas expressing one of them exclusively,while healthy T cells randomly express either TRBC1 or TRBC2. Here authors show structure-based design of a TRBC2-specific antibody,and depletion of malignant T cells carrying TRBC1 or TRBC2 with CAR-T cells against the cognate receptor chain in murine models. View Publication

BackgroundRadiation therapy is the standard of care for central nervous system tumours. Despite the success of radiation therapy in reducing tumour mass,irradiation (IR)-induced vasculopathies and neuroinflammation contribute to late-delayed complications,neurodegeneration,and premature ageing in long-term cancer survivors. Mesenchymal stromal cells (MSCs) are adult stem cells that facilitate tissue integrity,homeostasis,and repair. Here,we investigated the potential of the iPSC-derived MSC (iMSC) secretome in immunomodulation and vasculature repair in response to radiation injury utilizing human cell lines.MethodsWe generated iPSC-derived iMSC lines and evaluated the potential of their conditioned media (iMSC CM) to treat IR-induced injuries in human monocytes (THP1) and brain vascular endothelial cells (hCMEC/D3). We further assessed factors in the iMSC secretome,their modulation,and the molecular pathways they elicit.ResultsIncreasing doses of IR disturbed endothelial tube and spheroid formation in hCMEC/D3. When IR-injured hCMEC/D3 (IR ? 5 Gy) were treated with iMSC CM,endothelial cell viability,adherence,spheroid compactness,and proangiogenic sprout formation were significantly ameliorated,and IR-induced ROS levels were reduced. iMSC CM augmented tube formation in cocultures of hCMEC/D3 and iMSCs. Consistently,iMSC CM facilitated angiogenesis in a zebrafish model in vivo. Furthermore,iMSC CM suppressed IR-induced NF?B activation,TNF-? release,and ROS production in THP1 cells. Additionally,iMSC CM diminished NF-kB activation in THP1 cells cocultured with irradiated hCMEC/D3,iMSCs,or HMC3 microglial lines. The cytokine array revealed that iMSC CM contains the proangiogenic and immunosuppressive factors MCP1/CCL2,IL6,IL8/CXCL8,ANG (Angiogenin),GRO?/CXCL1,and RANTES/CCL5. Common promoter regulatory elements were enriched in TF-binding motifs such as androgen receptor (ANDR) and GATA2. hCMEC/D3 phosphokinome profiling revealed increased expression of pro-survival factors,the PI3K/AKT/mTOR modulator PRAS40 and ?-catenin in response to CM. The transcriptome analysis revealed increased expression of GATA2 in iMSCs and the enrichment of pathways involved in RNA metabolism,translation,mitochondrial respiration,DNA damage repair,and neurodevelopment.ConclusionsThe iMSC secretome is a comodulated composite of proangiogenic and immunosuppressive factors that has the potential to alleviate radiation-induced vascular endothelial cell damage and immune activation.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13287-024-03847-5. View Publication

IntroductionRetinal ganglion cells (RGCs) are susceptible to degenerative conditions such as glaucoma and traumatic optic neuropathies,which lead to vision loss. MicroRNA-21-5p has demonstrated potential neuroprotective effects,but its mechanisms in optic nerve injury remain underexplored. This study evaluates the neuroprotective role of microRNA-21-5p derived from induced pluripotent stem cells (iPSCs) in an optic nerve crush (ONC) model.Materials and methodsIn vitro qPCR demonstrated that the expression of microRNA-21-5p was increased in the co-culture medium of RGCs and iPSCs. Subsequently,in the in vivo experiments,we used a microRNA-21-5p agonist to assess its protective effects on RGCs. RNA sequencing was then performed in a mouse ONC model after treatment with a microRNA-21-5p agonist to explore the mechanisms underlying its neuroprotective effects on RGCs.ResultsAs demonstrated in our previous experiments,the RGCs-iPSCs co-culture group led to a higher survival rate of RGCs,as indicated by live/dead cell staining,compared to the RGCs-only group. Quantitative PCR (qPCR) results revealed a significant increase in the expression of microRNA-21-5p in the medium of the RGCs-iPSCs co-culture group. Furthermore,the survival rate of mouse retinal RGCs treated with a microRNA-21-5p agonist was significantly greater than that of the control group. Lastly,RNA sequencing of the retina from microRNA-21-5p agonist-treated mice indicated that microRNA-21-5p plays a protective role in RGCs by downregulating the expression of several genes,including Irf1,Ccl4,Itk,Cxcr2,Dclre1c,Traf1,Traf2,Rbl1,Cxcl5,Cxcl3,Cxcl1,Cxcl9,Il2rg,Cd3e,Cd3d,Cxcl10,Ccl5,Ccl12,Tap1,and Cxcr4.ConclusionMicroRNA-21-5p derived from iPSCs can enhance the survival rate of RGCs in the ONC model. This suggests that microRNA-21-5p may represent a novel and effective strategy for repairing RGC damage. Such a strategy could potentially be realized through the modulation of apoptosis,T-cell regulatory pathways,or TNF-? signaling.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12886-025-04244-z. View Publication