Engineering topics

Zhao, Yue

Publications and source records attributed to Zhao, Yue.

5 records

DOE OSTI2025

Engineered IL-18 variants with half-life extension and improved stability for cancer immunotherapy

Background The pro-inflammatory cytokine, interleukin-18 (IL-18), plays an instrumental role in bolstering anti-tumor immunity. However, the therapeutic application of IL-18 has been limited due to its susceptibility to neutralization by IL-18 binding protein (IL-18BP), short in vivo half-life, and unfavorable physicochemical properties. Methods In order to overcome the poor drug-like properties of IL-18, we installed an artificial disulfide bond, removed the native, unpaired cysteines, and fused the stabilized cytokine to an IgG Fc domain. The stability, potency, pharmacokinetic and pharmacodynamic properties as well as efficacy of disulfide-stabilized IL-18 Fc-fusion (dsIL-18-Fc) were assessed via in vitro and in vivo studies. Results The stability and mammalian host cell production yields of dsIL-18-Fc were improved, compared to the wild-type (WT) cytokine, while maintaining its biological potency and interactions with IL-18 receptor α (IL-18Rα) and IL-18BP. Recombinant fusion of the cytokine to an IgG Fc domain provided extended half-life. Notably, despite maintaining sensitivity to IL-18BP, dsIL-18-Fc was effective at activating both T and natural killer (NK) cells, and elicited a strong anti-tumor response, either as a single agent, or in conjunction with anti-programmed cell death-ligand 1 (anti-PD-L1) therapy. Conclusions We engineered IL-18 for reinforced stability, extended half-life, and improved manufacturability. The therapeutic benefit of dsIL-18-Fc, coupled with a more favorable manufacturability profile and enhanced drug-like properties, underscores the potential utility of this engineered cytokine in cancer immunotherapy.

Immunology↗

DOE OSTI2025

Cohort-based pan-cancer analysis and experimental studies reveal ISG15 gene as a novel biomarker for prognosis and immunotherapy efficacy prediction

Abstract ISG15, an interferon-stimulated ubiquitin-like protein, plays a multifaceted role in tumorigenesis and immune regulation. This study comprehensively evaluates ISG15 as a prognostic biomarker and predictor of immunotherapy response through pan-cancer bioinformatics analysis and experimental validation. By integrating multiomics data from TCGA, GEO, and clinical cohorts, we found that ISG15 is significantly overexpressed in multiple cancers and generally correlates with poor prognosis. Elevated ISG15 expression is associated with increased immune checkpoint gene expression, particularly PD-L1, and immune infiltration, notably M2-like tumor-associated macrophages. Immunohistochemistry and multiplexed immunofluorescence confirmed a strong positive correlation between ISG15, PD-L1, and M2-TAM infiltration in lung and gastric cancer samples. Functional analysis at the single-cell level revealed significant associations between ISG15 and tumor proliferation, angiogenesis, and immune suppression. Immunotherapy cohort analysis demonstrated that tumors with high ISG15 expression responded favorably to PD-L1 inhibitors but exhibited resistance to CTLA-4 blockade, findings further validated in lung cancer patients receiving anti-PD-1 therapy. These results suggest that ISG15 is a promising biomarker for prognosis and immunotherapy response prediction across cancers. Its integration into clinical decision-making may enhance personalized treatment strategies, improve immunotherapy outcomes, and provide new insights into the tumor immune microenvironment, cancer progression, and potential therapeutic targets for future drug development.

Immunology↗

DOE OSTI2024

Dark Photon Dark Matter and Low-frequency Gravitational-wave Detection with Gaia-like Astrometry

Astrometric surveys offer us a method for searching for elusive cosmic signatures, such as ultralight dark photon dark matter and gravitational waves (GWs), by observing the temporal change of stars’ apparent locations. The detection capabilities of such surveys rapidly decrease at low frequencies, because the signals become hardly distinguishable from the background motion of stars. In this work, we find that the background motion can be well described by a linear model over time, based on which we propose a linear background subtraction scheme. Compared to the conventional quadratic subtraction, the advantage of linear subtraction emerges within the frequency range below 6 × 10 −9 Hz. Taking dark photons with purely gravitational interactions, dark photons with additional U(1) B or U(1) B−L gauge interactions, and low-frequency GWs as examples, we illustrate that the linear subtraction scheme can result in an enhancement of more than 1 order of magnitude in the exclusion limits of Gaia-like experiments in the low-frequency range.

Astrometry↗

DOE OSTI2024

Long-baseline quantum sensor network as dark matter haloscope

Ultralight dark photons constitute a well-motivated candidate for dark matter. A coherent electromagnetic wave is expected to be induced by dark photons when coupled with Standard-Model photons through kinetic mixing mechanism, and should be spatially correlated within the de Broglie wavelength of dark photons. Here we report the first search for correlated dark-photon signals using a long-baseline network of 15 atomic magnetometers, which are situated in two separated meter-scale shield rooms with a distance of about 1700 km. Both the network’s multiple sensors and the shields large size significantly enhance the expected dark-photon electromagnetic signals, and long-baseline measurements confidently reduce many local noise sources. Using this network, we constrain the kinetic mixing coefficient of dark photon dark matter over the mass range 4.1 feV-2.1 peV, which represents the most stringent constraints derived from any terrestrial experiments operating over the aforementioned mass range. Our prospect indicates that future data releases may go beyond the astrophysical constraints from the cosmic microwave background and the plasma heating.

72 PHYSICS OF ELEMENTARY PARTICLES AND FIELDS↗

NASA NTRS2007

Auxiliary Components for Kilopixel Transition Edge Sensor Arrays

We have fabricated transition edge sensor bolometer focal plane arrays sensitive to mm-submillimeter (0.1-3 THz) radiation for the Atacama Cosmology Telescope (ACT), which will probe the cosmic microwave background at 0.147,0.215, and 0.279 GHz. Central to the performance of these bolometers is a set of auxiliary resistive components. Here we discuss shunt resistors, which allow for tight optimization of bolometer time constant and sensitivity. Our shunt resistors consist of AuPd strips grown atop of interdigitated superconducting MoN, wires. We can tailor the shunt resistance by altering the dimensions of the AuPd strips and the pitch and width of the MoN, wires and can fabricate over 1000 shunts on a single 4" wafer. By modeling the resistance dependence of these parameters, a variety of different 0.77 +I-0.13 mOhm shunt resistors have been fabricated. This variety includes different shunts possessing MoN, wires with wire width equal to 1.5 and 10 microns and pitch equal to 4.5 and 26 microns, respectively. Our ability to set the resistance of the shunts hints at the scalability of our design. We have also integrated a Si02 capping layer into our shunt resistor fabrication scheme, which inhibits metal corrosion and eventual degradation of the shunt. Consequently, their robustness coupled with their high packing density makes these resistive components attractive for future kilopixel detector arrays.

Brown, Ari-David↗