Abstract Title
Engineering natural killer cells for personalised immune-cellular therapeutics
Abstract
Natural Killer (NK) cells are key to cancer immunosurveillance, particularly in settings of metastasis. They are dependent on the cytokine IL-15 for their survival, development, and function, with ablation of the IL-15 signalling inhibitor CIS (Cish), shown to enhance NK cell anti-tumour immunity by increasing NK cell fitness in the tumour microenvironment (TME). The TME has also been shown to impair NK cell fitness via the production of immunosuppressive transforming growth factor (TGF)-β, even in the presence of high IL-15 signalling. Here, taking advantage of sophisticated proteomics and transcriptomics methods with computational biology analysis we identified an unexpected interaction between CIS and the TGF-β signalling pathway in NK cells. Independently, for the first time a Cish- and Tgfbr2- double-deficient NK cells were generated by our group, which displayed both hyper-responsiveness to IL-15 and hypo-responsiveness to TGF-β, with dramatically enhanced immunity against multiple mouse models of cancer. Remarkable, when both these immunosuppressive genes are simultaneously deleted in NK cells, mice are largely resistant to tumour development and this resistance is dependent on NK cell hyper-activity. This study contributes to the understanding of how targeting multiple suppressive pathways unveils a new immunotherapy approach that might have broad therapeutic interventions, particularly by enhancing NK cell effector functions during disease.
Title
Strategic design of Fe and N co-doped hierarchically porous carbon as superior ORR catalyst: From the perspective of nanoarchitectonics
Abstract
Sluggish oxygen reduction reaction (ORR) in hydrogen fuel cells largely limits the scope of choice for its electrocatalysts to Platinum-group metal (PGM) species of high cost, low earth abundance, and poor stability. Consequently, it is necessary to develop novel ORR electrocatalysts with cheap and earth-abundant metals to replace expensive PGM-based catalysts. Zeolitic imidazolate framework-8 (ZIF-8), a type of metal-organic framework, can be easily converted into nitrogen-doped porous carbon by a direct-carbonization process. With large surface area, moderate electrical conductivity, and abundant nitrogen dopants, ZIF-8-derived porous carbons have been heavily exploited to synthesize PGM-free ORR catalysts. Its highly microporous structure, however, severely restricts the efficient diffusion of substances, hence rendering a significant portion of the surface area electrochemically redundant. Therefore, the nanoarchitecture of ZIF-8-derived porous carbon must be designed and synthesized in a more strategic way to expose as much surface area as possible to the surrounding electrochemical environment. Herein, a novel ZIF-8-derived hierarchically porous carbon with a double-shelled structure is synthesized to maximize electrochemically accessible/active surface area. Next, its carbon scaffold is doped with Fe atoms to form highly active Fe-Nx sites, hence achieving dramatic improvement in ORR catalytic activity comparable to that of commercial 20 wt% Pt/C in alkaline electrolyte. |
