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关键词： T cell receptor   HLA   CDR3   Deep Learning  

摘要： Understanding the relationship between T cell receptors (TCRs) and human leukocyte antigens (HLAs) is essential to elucidate the specificity of the immune response, uncover mechanisms of autoimmunity, and advance targeted immunotherapies. We have previously developed a deep learning method, DePTH (Deep Learning Prediction of TCR-HLA associations), to predict the association between a TCR and an HLA based on their amino acid sequences. In this work, we demonstrate that DePTH can make accurate predictions of TCR-HLA associations in two additional datasets. We have also investigated the influence of two confounders: TCR generation probability and the sequence length of CDR3 (Complementarity-Determining Region 3), and conclude that DePTH learns additional information beyond these two factors. Building on these insights, we combined training data from the two new datasets to train two new versions of DePTH: DePTH 2.0 and DePTH 2.1.

关键词： HLA-C*12:02:57   Indian   next generation sequencing   novel allele  

摘要： The novel allele HLA-C*12:02:57 differs from HLA-C*12:02:02:01 by a one nucleotide change A > T in exon 4 (CCA > CCT).

关键词： allosteric inhibitor   DNA-encoded chemical library   DEL   IL-17   protein-protein interactions  

摘要： A novel series of inhibitors of the interaction of IL-17A with its cognate receptor has been discovered using DNA-encoded library (DEL) technology. The lead compound (JNJ627, Compound 1) of the series occupies the interior interface of the IL-17A homodimer and disables receptor binding. The mechanism of action involves allosteric disruption of the IL-17A quaternary structure to prevent adoption of the receptor-binding conformation, rather than direct orthosteric inhibition at the receptor-binding site. Molecules of this series exhibit remarkably slow on-rate kinetics and potent inhibition of IL-17A signaling in human primary cells.

关键词： Apoptosis   Cytochrome c   Extrinsic pathway   Intrinsic pathway   TNF-alpha   Vitamin c  

摘要： This study investigates the effect of vitamin C on cytochrome c and TNF-alpha expression, representing intrinsic and extrinsic apoptotic pathways in B16-F10 melanoma cells. B16-F10 melanoma cells (ATCC (R) CRL-6475 (TM)) were treated with vitamin C for 12 and 24 h. Expression of cytochrome c, TNF-alpha, caspase-3, and caspase-9 proteins was evaluated using in-cell western (ICW) assay. RT-qPCR was used to assess gene expression of Caspase-8, IL-6, PARP-gamma, and TGF-beta 1. Morphological signs of cell death appeared within 12 h. A significant increase in cytochrome c expression at 3,000 mu M concentrations of vitamin C was observed (p = 0.002), along with increases at 3,500 mu M (p = 0.023), 4,000 mu M (p = 0.0001), and 5,000 mu M (p = 0.0001). Caspase-3 expression significantly increased at 3,000 mu M (p = 0.012) and 5,000 mu M (p = 0.048), while caspase-9 was not significant. TNF-alpha expression also increased significantly from 3,000 to 5,000 mu M (all p < 0.01). Caspase-8 and PARP-gamma mRNA levels were upregulated at 3,000 and 5,000 M (p < 0.05). IL-6 and TGF-beta 1 changes further supported apoptosis activation. Vitamin C induces apoptosis in B16-F10 melanoma cells via intrinsic and extrinsic pathways, particularly at 3,000 and 5,000 M concentrations, as shown by cytochrome c, TNF-alpha, and caspase-3 expression.

关键词： Triple-negative breast cancer   Type I IFN pathway   Combination therapy   Immune cytotoxicity   Doxorubicin  

摘要： Objective This study aimed to investigate the synergistic antitumor effects and immunoregulatory functions of the SUMOylation inhibitor TAK-981 in combination with the chemotherapeutic agent doxorubicin (DOX) in triple-negative breast cancer (TNBC), as well as to evaluate the safety of this combination strategy, particularly its mitigating effect on DOX-induced cardiotoxicity. Methods In vitro experiments were conducted to assess the effects of TAK-981 and DOX, both alone and in combination, on the type I interferon (IFN I) signaling pathway, cell proliferation, and apoptosis in TNBC cells. Mechanistic studies were performed to explore their impact on the IFN I/JAK1/STAT1 axis and the expression of the downstream NKG2D ligand NKG2DL (ULBP2). In vivo animal models were used to evaluate the antitumor efficacy of the combination therapy, its effect on natural killer (NK) cell activity, systemic toxicity, with a focus on its cardioprotective effects. Results TAK-981 activated IFN I signaling, and DOX further enhanced IFN I pathway activity. The two drugs demonstrated a synergistic effect, significantly inducing apoptosis and inhibiting proliferation in TNBC cells. Mechanistically, the TAK-981 and DOX combination targeted the IFN I/JAK1/STAT1 signaling axis, downregulating the expression of the NKG2D ligand (ULBP2) through suppression of the NF-kappa B pathway. In vivo experiments confirmed that the combination therapy effectively inhibited tumor growth, enhanced NK cell activity, and did not increase systemic toxicity. Notably, TAK-981 significantly alleviated DOX-induced cardiotoxicity, improved cardiac function, and reduced fibrosis. Conclusion The combination of an immunomodulatory agent with chemotherapy represents a novel therapeutic strategy for TNBC. TAK-981 not only synergizes with DOX to produce antitumor immun effects but also significantly mitigates DOX-induced cardiotoxicity, offering a promising new direction for improving the efficacy and safety of TNBC tr

摘要： In this issue of Developmental Cell, Ma et al. show that embryonically derived VSIG4(+)macrophages suppress CD8(+) T cell responses across cancers. They identify IL-11 as a key effector and MEF2C as a transcriptional regulator of VSIG4(+) macrophages, highlighting new therapeutic avenues for targeting immunosuppressive tumor-associated macrophages to improve immunotherapy outcomes.

关键词： bacterial vector   IL-15   myeloid cells   STING   tumor microenvironment  

摘要： STACT is a modular, genetically engineered live attenuated S. Typhimurium bacterial platform that enables tissue-specific localization and cell-targeted delivery of large, multiplexed payloads via systemic administration. It has been engineered to minimize systemic toxicity and to enrich in the tumor microenvironment (TME) via metabolic dependency and showed a decreased systemic inflammatory cytokine profile compared to its parent strain VNP20009. ACTM-838 utilizes the STACT platform to deliver IL-15/IL15Rα and a constitutively active STING to tumor-resident phagocytic antigen-presenting cells. Upon intravenous (IV) dosing to tumor-bearing mice, ACTM-838 distributed and enriched in the TME, exhibited specific uptake in tumor-resident phagocytic cells and led to expression of human IL-15/IL15Rα and murine IFNα in the tumor. ACTM-838 induced comprehensive TME changes to an immune permissive anti-tumor phenotype with a decrease in exhausted T-cells and Tregs and an increase in cytolytic T-cells and MHCII-high proliferating myeloid cells. ACTM-838-treated tumors exhibited upregulated anti-tumor innate and adaptive immunity expression profiles, T-, NK- and B-cell infiltration and downregulated cell cycle, DNA damage and TGFβ responses. Single-cell RNAseq and flow cytometry data confirmed activation and infiltration of both innate and adaptive immune cells. ACTM-838 showed durable anti-tumor efficacy in multiple murine tumor models and synergized with anti-PD1 therapy in combination.

摘要： IL-21/IL-21R signaling is crucial in various immune diseases and cellular development, however, its role in bacterial pneumonia remains unclear. Here, IL-21R knockout (IL-21R-/-) mice were more susceptible to Actinobacillus pleuropneumoniae (APP) than wild-type (WT) mice. High-dimensional mass cytometry analysis revealed that IL-21R deficiency inhibited neutrophil activation, decreased the numbers of monocytes and proinflammatory macrophages, and augmented the defective CD3low T cells in the lungs. Intracellular cytokine staining showed decreased IFN-gamma/TNF-alpha/IL-6 production in IL-21R-/- mice, particularly in CD8(+) T cells. Furthermore, a previously unrecognized Ly6C+Ly6G+CD4+ T cell subset emerged only in the lungs of WT mice post-APP infection, which was in an activated status with stronger secretion capacities of IL-10, IL-21, granzyme B, and perforin by flow cytometry. These cells polarized macrophages into M2- or M1- phenotype without/with infection, respectively, and enhanced proliferation, phagocytosis, and macrophage extracellular traps/ROS-mediated bactericidal activity of macrophages against-APP, Klebsiella pneumoniae, or Escherichia coli infection. Thus, our study demonstrated that IL-21 drives the differentiation of neutrophils, monocytes, and macrophages into pro-inflammatory subsets. IL-21-induced Ly6C+Ly6G+CD4+ T cells cooperate with macrophages to enhance bacterial clearance, providing a promising target for preventing bacterial pneumonia.

关键词： cancer immunotherapy   oncolytic virus   T cell senescence   tumor microenvironment   type I interferon  

摘要： Solid tumors often suppress antitumor immune responses by promoting various dysfunctional CD8+ T cell states, which limit the effectiveness of T-cell-based immunotherapy. However, the mechanisms that promote these states have not been fully characterized. It is demonstrated that spontaneous priming responses during tumor growth can produce memory T cell reservoirs that are conducive to poor proliferative responsiveness during boosting vaccination. Surprisingly, when type I interferon (IFN-I) signaling is impeded, boosting vaccination can elicit robust proliferative responses from tumor-primed memory T cells and promote tumor control. This is observed in multiple tumor types and target antigens. In contrast to conventional memory T cells, tumor-primed memory T cells are unique in their pre-encoded responsiveness to IFN-I and show enrichment of pathways pertaining to DNA repair and cell cycle arrest. Tumor-primed memory T cells up-regulate p21 expression and blockade of either p21 or IFN-I can alleviate this effect to improve their proliferative capacity during boosting vaccination. Characterization of tumor-primed memory T cells revealed transcriptional and phenotypic features of cellular senescence, where higher senescence severity correlated with higher responsiveness to IFN alpha/beta receptor blockade. Overall, IFN-I hyperresponsiveness may be a unique feature of senescent tumor-primed memory T cells that can exacerbate their dysfunction during cancer vaccination.

关键词： alloimmunization   HLA   HNA   HPA   neonatal neutropenia   neonatal thrombocytopenia  

摘要： Background Fetal/neonatal alloimmune thrombocytopenia (FNAIT) and neonatal alloimmune neutropenia (NAIN) result from maternal alloantibodies targeting fetal human platelet antigen (HPA) and human neutrophil antigen (HNA) antigens, respectively. However, increasing evidence supports the pathogenic role of HLA class I alloantibodies in these conditions. Since the simultaneous occurrence of FNAIT and NAIN has not been systematically investigated, this study aimed to determine its prevalence, characterize the specificity and strength of associated alloantibodies, and correlate findings with neonatal cell *** Design and Methods In this cross-sectional study, 10,000 umbilical cord blood samples were analyzed for platelet and neutrophil counts. Neonates with thrombocytopenia and neutropenia were selected. Genotyping for HPA, HNA, and HLA class I was performed in mother-infant pairs to assess incompatibilities. Maternal sera were tested for anti-HPA, anti-HNA, and anti-HLA *** Ten cases (0.1%) of concurrent cytopenias were identified. Alloantibodies were detected in four cases: one with combined anti-HPA-5b, HNA-2, and HLA-A2 antibodies;and three with isolated high-mean fluorescence intensity (MFI) HLA antibodies (anti-HLA-A2, HLA-A3, HLA-B7). Anti-HLA-A2 was linked to the lowest neutrophil counts, and anti-HLA-B7 to severe thrombocytopenia. The estimated prevalence of simultaneous FNAIT and NAIN was 0.04% (1 in 2500 neonates).Discussion This is the first large-scale study to document the co-occurrence of FNAIT and NAIN. Our findings explore the serological and molecular features of these immune syndromes and underscore the potential pathogenic role of maternal anti-HLA class I antibodies, even in the absence of detectable anti-HPA or anti-HNA, and support including HLA testing in the diagnostic workup of neonatal cytopenias.