Targeting Gsk3a reverses immune evasion to enhance immunotherapy in hepatocellular carcinoma.

BACKGROUND: Immune escape is an important feature of hepatocellular carcinoma (HCC). The overall response rate of immune checkpoint inhibitors (ICIs) in HCC is still limited. Revealing the immune regulation mechanisms and finding new immune targets are expected to further improve the efficacy of immunotherapy. Our study aims to use CRISPR screening mice models to identify potential targets that play a critical role in HCC immune evasion and further explore their value in improving immunotherapy. METHODS: We performed CRISPR screening in two mice models with different immune backgrounds (C57BL/6 and NPG mice) and identified the immunosuppressive gene Gsk3a as a candidate for further investigation. Flow cytometry was used to analyze the impact of Gsk3a on immune cell infiltration and T-cell function. RNA sequencing was used to identify the changes in neutrophil gene expression induced by Gsk3a and alterations in downstream molecules. The therapeutic value of the combination of Gsk3a inhibitors and anti-programmed cell death protein-1 (PD-1) antibody was also explored. RESULTS: Gsk3a, as an immune inhibitory target, significantly promoted tumor growth in immunocompetent mice rather than immune-deficient mice. Gsk3a inhibited cytotoxic T lymphocytes (CTLs) function by inducing neutrophil chemotaxis. Gsk3a promoted self-chemotaxis of neutrophil expression profiles and neutrophil extracellular traps (NETs) formation to block T-cell activity through leucine-rich α-2-glycoprotein 1 (LRG1). A significant synergistic effect was observed when Gsk3a inhibitor was in combination with anti-PD-1 antibody. CONCLUSIONS: We identified a potential HCC immune evasion target, Gsk3a, through CRISPR screening. Gsk3a induces neutrophil recruitment and NETs formation through the intermediate molecule LRG1, leading to the inhibition of CTLs function. Targeting Gsk3a can enhance CTLs function and improve the efficacy of ICIs.

Effect of Magnetic Moment on Carrier Effective Mass and Transport in Magnetic Nd2Fe14B Composite Bi2Te3 Films.

A composite of magnetic and thermoelectric (TE) materials is one of the most popular methods to improve TE properties. However, the influential mechanism of the magnetic property on the carrier has not been clarified. In this study, Nd2Fe14B cylinders are used as the magnetic phase to regulate carrier behaviors in Bi2Te3 films. Roaming state Fe atoms in Nd2Fe14B provide some carriers. The VTe at the composite interface also provides carriers. These lead to the increase of carrier concentration and conductivity of the composite film. Meanwhile, the Lorentz force generated by the magnetic moment of Nd2Fe14B provides the carriers with a stronger energy, which results in the increase of carrier effective mass and thereby increases the Seebeck coefficient. Thus, the power factor of the magnetic composite film is improved by 366% compared with that of the pure Bi2Te3 film.