A novel LAG3 neutralizing antibody improves cancer immunotherapy by dual inhibition of MHC-II and FGL1 ligand binding.

LAG3 is an inhibitory immune checkpoint expressed on activated T and NK cells. Blocking the interaction of LAG3 with its ligands MHC-II and FGL1 renders T cells improved cytotoxicity to cancer cells. Current study generated a panel of LAG3 monoclonal antibodies (mAbs) through immunization of mice followed by phage display. Some of them bound to the D1-D2 domain of LAG3, which is known for the engagement of its ligands FGL1 and MHC-II. Three outperformers, M208, M226, and M234, showed stronger blocking activity than Relatlimab in the FGL1 binding. Furthermore, M234 showed dual inhibition of FGL1 (IC50 of 20.6 nM) and MHC-II binding (IC50 of 6.2 nM) to LAG3. In vitro functional tests showed that M234 significantly stimulated IFN-γ secretion from activated PBMC cells. In vivo studies in a mouse model of hepatocellular carcinoma xenografts demonstrated that combining M234 IgG with GPC3-targeted bispecific antibodies significantly improved efficacy. In addition, GPC3-targeted CAR-T cells secreting IL-21-M234 scFv fusion protein exhibited enhanced activity in inhibiting tumor growth and greatly increased the survival rate of mice. Taken together, M234 has potential in cancer immunotherapy and warrants further clinical trial.

Occurrence, transmission and risks assessment of pathogens in aquatic environments accessible to humans.

Pathogens are ubiquitously detected in various natural and engineered water systems, posing potential threats to public health. However, it remains unclear which human-accessible waters are hotspots for pathogens, how pathogens transmit to these waters, and what level of health risk associated with pathogens in these environments. This review collaboratively focuses and summarizes the contamination levels of pathogens on the 5 water systems accessible to humans (natural water, drinking water, recreational water, wastewater, and reclaimed water). Then, we showcase the pathways, influencing factors and simulation models of pathogens transmission and survival. Further, we compare the health risk levels of various pathogens through Quantitative Microbial Risk Assessment (QMRA), and assess the limitations of water-associated QMRA application. Pathogen levels in wastewater are consistently higher than in other water systems, with no significant variation for Cryptosporidium spp. among five water systems. Hydraulic conditions primarily govern the transmission of pathogens into human-accessible waters, while environmental factors such as temperature impact pathogens survival. The median and mean values of computed public health risk levels posed by pathogens consistently surpass safety thresholds, particularly in the context of recreational waters. Despite the highest pathogens levels found in wastewater, the calculated health risk is significantly lower than in other water systems. Except pathogens concentration, variables like the exposure mode, extent, and frequency are also crucial factors influencing the public health risk in water systems. This review shares valuable insights to the more accurate assessment and comprehensive management of public health risk in human-accessible water environments.

An immune cell atlas reveals the dynamics of human macrophage specification during prenatal development.

Macrophages are heterogeneous and play critical roles in development and disease, but their diversity, function, and specification remain inadequately understood during human development. We generated a single-cell RNA sequencing map of the dynamics of human macrophage specification from PCW 4-26 across 19 tissues. We identified a microglia-like population and a proangiogenic population in 15 macrophage subtypes. Microglia-like cells, molecularly and morphologically similar to microglia in the CNS, are present in the fetal epidermis, testicle, and heart. They are the major immune population in the early epidermis, exhibit a polarized distribution along the dorsal-lateral-ventral axis, and interact with neural crest cells, modulating their differentiation along the melanocyte lineage. Through spatial and differentiation trajectory analysis, we also showed that proangiogenic macrophages are perivascular across fetal organs and likely yolk-sac-derived as microglia. Our study provides a comprehensive map of the heterogeneity and developmental dynamics of human macrophages and unravels their diverse functions during development.

Distinct responses of Pseudomonas aeruginosa PAO1 exposed to different levels of polystyrene nanoplastics.

Large amounts of discarded plastics in the environment can be aged into microplastics and nanoplastics, which are not easily removed, posing potential nonnegligible risks to the ecosystem and human health. Although previous studies have revealed that nanoplastics have detrimental impacts on microorganisms, the potential molecular mechanisms of nanoplastic particles' effect on microbial growth and metabolism are still lacking. Here, multiple responses of Pseudomonas aeruginosa PAO1 (PAO1) to different levels of polystyrene nanoplastics (PS NPs) exposure were investigated by physiological experiments, live/dead staining, redox status, and genome-wide RNA sequencing. The results showed that PS NPs had dual effects on PAO1, and different concentrations of PS NPs demonstrated different effects on the growth and metabolism of PAO1. All levels of PS NPs had no obvious biocidal effect on PAO1. The production and consumption of ROS were in dynamic equilibrium and could be regulated genetically to ensure that the ROS level was in the biotolerable range. 20 and 50 mg/L of PS NPs severely inhibited the nitrate reduction, while 0.1 mg/L of PS NPs promoted the denitrification and TCA cycle. Meanwhile, 20 and 50 mg/L of PS NPs resulted in intense down-regulation of genes involved in denitrification. In contrast, the expression of genes involved in respiration is promoted with generated energy to withstand stress from high-level PS NPs, coinciding with the physiological results. In addition, our results showed that PS NPs concentrations of 20 and 50 mg/L exposure substantially up-regulated the expression of genes encoding for flagellar biosynthesis and biofilm formation to tackle the stress. Our findings would provide new insights into the interactions between environmental bacteria and PS NPs at the transcriptional level, thereby enhancing our understanding of the potential risks of PS NPs to microbial ecosystems and public health.