Developing novel approaches to reverse the drug resistance of tumor-repopulating cells (TRCs) or stem cell-like cancer cells is an urgent clinical need to improve outcomes of cancer patients. Here we show an innovative approach that reverses drug resistance of TRCs using tumor cell-derived microparticles (T-MPs) containing anti-tumor drugs. TRCs, by virtue of being more deformable than differentiated cancer cells, preferentially take up T-MPs that release anti-tumor drugs after entering cells, which in turn lead to death of TRCs. The underlying mechanisms include interfering with drug efflux and promoting nuclear entry of the drugs. Our findings demonstrate the importance of tumor cell softness in uptake of T-MPs and effectiveness of a novel approach in reversing drug resistance of TRCs with promising clinical applications.

Interactions with the immune system may lead tumorigenic cells into dormancy. However, the underlying molecular mechanism is poorly understood. Using a 3D fibrin gel model, we show that IFN-γ induces tumour-repopulating cells (TRCs) to enter dormancy through an indolamine 2,3-dioxygenase 1 (IDO1)-kynurenine (Kyn)-aryl hydrocarbon receptor (AhR)-p27 dependent pathway. Mechanistically, IFN-γ signalling triggers differentiated tumour cell apoptosis via STAT1; however, when IDO1 and AhR are highly expressed as in TRCs, IFN-γ results in IDO1/AhR-dependent p27 induction that prevents STAT1 signalling, thus suppressing the process of cell death and activating the dormancy program. Blocking the IDO/AhR metabolic circuitry not only abrogates IFN-γ-induced dormancy but also results in enhanced repression of tumour growth by IFN-γ-induced apoptosis of TRCs both in vitro and in vivo. These data present a previously unrecognized mechanism of inducing TRC dormancy by IFN-γ, suggesting a potential effective cancer immunotherapeutic modality through the combination of IFN-γ and IDO/AhR inhibitors.

Tumor antigens and innate signals are vital considerations in developing new therapeutic or prophylactic antitumor vaccines. The role or requirement of intact tumor cells in the development of an effective tumor vaccine remains incompletely understood. This study reveals the mechanism by which tumor cell-derived microparticles (T-MP) can act as a cell-free tumor vaccine. Vaccinations with T-MPs give rise to prophylactic effects against the challenge of various tumor cell types, while T-MP-loaded dendritic cells (DC) also exhibit therapeutic effects in various tumor models. Such antitumor effects of T-MPs are perhaps attributable to their ability to generate immune signaling and to represent tumor antigens. Mechanically, T-MPs effectively transfer DNA fragments to DCs, leading to type I IFN production through the cGAS/STING-mediated DNA-sensing pathway. In turn, type I IFN promotes DC maturation and presentation of tumor antigens to T cells for antitumor immunity. These findings highlight a novel tumor cell-free vaccine strategy with potential clinical applications.

CD8 memory T (Tm) cells are fundamental for protective immunity against infections and cancers . Metabolic activities are crucial in controlling memory T-cell homeostasis, but mechanisms linking metabolic signals to memory formation and survival remain elusive. Here we show that CD8 Tm cells markedly upregulate cytosolic phosphoenolpyruvate carboxykinase (Pck1), the hub molecule regulating glycolysis, tricarboxylic acid cycle and gluconeogenesis, to increase glycogenesis via gluconeogenesis. The resultant glycogen is then channelled to glycogenolysis to generate glucose-6-phosphate and the subsequent pentose phosphate pathway (PPP) that generates abundant NADPH, ensuring high levels of reduced glutathione in Tm cells. Abrogation of Pck1-glycogen-PPP decreases GSH/GSSG ratios and increases levels of reactive oxygen species (ROS), leading to impairment of CD8 Tm formation and maintenance. Importantly, this metabolic regulatory mechanism could be readily translated into more efficient T-cell immunotherapy in mouse tumour models.

Astragalus polysaccharide (APS) has been reported to increase insulin sensitization and to ameliorate diabetes in animal models, and studies have demonstrated that this effect may be correlated with its anti-inflammatory roles in vivo and in vitro. However, the potential pharmacological mechanisms of APS in anti-inflammatory regulation are still poorly understood. Herein, RAW264.7 cells treated with APS showed anti-inflammatory effects. Interleukin (IL)-10 protein levels and expression of most of the anti-inflammatory genes, including IL-10, macrophage mannose receptor (MMR), arginase, Dectin-1, YM-1 and YM-2, were significantly increased after treatment with APS for 24 h. Furthermore, to determine whether APS plays a potential role in RAW264.7 cell inflammation, we pretreated RAW264.7 cells with APS in the presence of palmitate. The results showed that APS markedly recovered the impairment of AMPK activity induced by palmitate. Furthermore, APS induced IL-10 protein production and anti-inflammatory gene expression of IL-10, MMR, Dectin-1, arginase, YM-1 and YM-2. Additionally, APS inhibited IL-1β protein production and expression of most of the pro-inflammatory genes, such as IL-1β, iNOS, MCP-1, IL-6 and CD11c but not tumor necrosis factor (TNF)-α. Notably, the effect of APS on inflammatory genes, except for TNF-α, was abrogated when AMPK activity was inhibited using a DN-AMPK plasmid. These results suggest that APS effectively ameliorates palmitate-induced pro-inflammatory responses through AMPK activity.

Model-based systems engineering (MBSE) provides an important capability for managing the complexities of system development. MBSE empowers the formalism of system architectures for supporting model-based requirement elicitation, specification, design, development, testing, fielding, etc. However, the modeling languages and techniques are heterogeneous, even within the same enterprise system, which leads to difficulties for data interoperability. The discrepancies among data structures and language syntaxes make information exchange among MBSE models more difficult, resulting in considerable information deviations when connecting data flows across the enterprise. Therefore, this article presents an ontology based upon graphs, objects, points, properties, roles, and relationships with extensions (GOPPRRE), providing metamodels that support the various MBSE formalisms across lifecycle stages. In particular, knowledge graph models are developed to support unified model representations to further implement ontological data integration based on GOPPRRE throughout the entire lifecycle. The applicability of the MBSE formalism is verified using quantitative and qualitative approaches. Moreover, the GOPPRRE ontologies are used to create the MBSE formalisms in a domain-specific modeling tool, MetaGraph, for evaluating its availability. The results demonstrate that the proposed ontology supports the formal structures and descriptive logic of the systems engineering lifecycle.

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Cognitive Twins (CT) are proposed as Digital Twins (DT) with augmented semantic capabilities for identifying the dynamics of virtual model evolution, promoting the understanding of interrelationships between virtual models and enhancing the decision-making based on DT. The CT ensures that assets of Internet of Things (IoT) systems are well-managed and concerns beyond technical stakeholders are addressed during IoT system development. In this paper, a Knowledge Graph (KG) centric framework is proposed to develop CT. Based on the framework, a future tool-chain is proposed to develop the CT for the initiatives of H2020 project FACTLOG. Based on the comparison between DT and CT, we infer the CT is a more comprehensive approach to support IoTbased systems development than DT.