Immune checkpoint blockade resistance narrows the efficacy of cancer immunotherapies, but the underlying mechanism remains elusive. Delineating the inherent mechanisms of anti-PD1 resistance is ...important to improve outcome of patients with advanced HCC.
The level of cricTMEM181 was measured in HCC patients with anti-PD1 therapy by RNA sequencing and then confirmed by qPCR and Sanger sequencing. Immune status in tumor microenvironment of HCC patients or mice models was evaluated by flow cytometry and IHC. Exosomes from HCC cell lines were isolated by ultracentrifugation, and their internalization by macrophage was confirmed by immunofluorescence. The underlying mechanism of HCC-derived exosomal circTMEM181 to macrophage was confirmed by SILAC, RNA FISH and RNA immunoprecipitation. The ATP-ADO pathway amplified by HCC-macrophage interaction was evaluated through ATP, AMP and ADO measurement and macrophage-specific CD39 knockout mice. The role of circTMEM181 in anti-PD1 therapy and its clinical significance were also determined in our retrospective HCC cohorts.
Here, we found that circTMEM181 was elevated in hepatocellular carcinoma (HCC) patients responding poorly to anti-PD1 therapy and in HCC patients with a poor prognosis after operation. Moreover, we also found that high exosomal circTMEM181 favored the immunosuppressive microenvironment and endowed anti-PD1 resistance in HCC. Mechanistically, exosomal circTMEM181 sponged miR-488-3p and upregulated CD39 expression in macrophages. Using macrophage-specific CD39 knockout mice and pharmacologic approaches, we revealed a novel mode of anti-PD1 resistance in HCC. We discovered that cell-specific CD39 expression in macrophages and CD73 expression in HCC cells synergistically activated the eATP-adenosine pathway and produced more adenosine, thereby impairing CD8
T cell function and driving anti-PD1 resistance.
In summary, HCC-derived exosomal circTMEM181 contributes to immunosuppression and anti-PD1 resistance by elevating CD39 expression, and inhibiting the ATP-adenosine pathway by targeting CD39 on macrophages can rescue anti-PD1 therapy resistance in HCC.
Recent evidence suggests that innate and adaptive immunity play a crucial role in Parkinson's disease (PD). However, studies regarding specific immune cell classification in the peripheral blood in ...PD remain lacking. Therefore, we aimed to explore the different immune status in patients with PD at different ages of onset. We included 22 patients; among them were 10 who had early-onset PD (EOPD) and 12 had late-onset PD (LOPD) and 10 young healthy controls (YHCs) and 8 elder HCs (EHCs). Mass cytometry staining technology was used to perform accurate immunotyping of cell populations in the peripheral blood. Motor symptoms and cognitive function were assessed using the Unified Parkinson's Disease Rating Scale (UPDRS) III score and Mini-mental State Examination (MMSE) score, respectively. T test and ANOVA statistical analysis were performed on the frequency of annotated cell population. Linear regression model was used to analyze the correlation between clusters and clinical symptoms. We characterized 60 cell clusters and discovered that the immune signature of PD consists of cluster changes, including decreased effector CD8
T cells, lower cytotoxicity natural killer (NK) cells and increased activated monocytes in PD patients. In summary, we found that CD8
T cells, NK cells, and monocytes were associated with PD. Furthermore, there may be some differences in the immune status of patients with EOPD and LOPD, suggesting differences in the pathogenesis between these groups.
Lymphoid‐specific helicase (LSH) is overexpressed in tumor tissues and its overexpression is associated with poor prognosis in several cancers. However, the role and molecular mechanism of LSH in ...hepatocellular carcinoma (HCC) remains largely unknown. Herein, we report that LSH was overexpressed in tumor tissues of HCC, and overexpression of LSH was associated with poor prognosis from a public HCC database, and validated by clinical samples from our department. Ectopic LSH expression promoted the growth of HCC cells in vivo and in vitro. Mechanistically, LSH overexpression promoted tumor growth by activating transcription of centromere protein F (CENPF). Clinically, overexpression of LSH and/or CENPF correlated with shorter overall survival and higher cumulative recurrence rates of HCC. In conclusion, LSH promotes tumor growth of HCC through transcriptional regulation of CENPF expression. Therefore, LSH may be a novel predictor for prognosis and a potential therapeutic target for HCC.
In the present study, we first evaluated LSH as a potential prognostic marker in hepatocellular carcinoma. We also investigated the cellular and molecular mechanism, especially in cancer invasion and metastasis. Herein, we initially determined a novel mechanism involving protein‐DNA binding between LSH and the CENPF gene.
Activation of the phagocytosis of macrophages to tumor cells is an attractive strategy for cancer immunotherapy, but the effectiveness is limited by the fact that many tumor cells express an ...increased level of anti‐phagocytic signals (e.g., CD47 molecules) on their surface. To promote phagocytosis of macrophages, a pro‐phagocytic nanoparticle (SNPACALR&aCD47) that concurrently carries CD47 antibody (aCD47) and a pro‐phagocytic molecule calreticulin (CALR) is constructed to simultaneously modulate the phagocytic signals of macrophages. SNPACALR&aCD47 can achieve targeted delivery to tumor cells by specifically binding to the cell‐surface CD47 and block the CD47‐SIRPα pathway to inhibit the “don't eat me” signal. Tumor cell‐targeted delivery increases the exposure of recombinant CALR on the cell surface and stimulates an “eat me” signal. Simultaneous modulation of the two signals enhances the phagocytosis of 4T1 tumor cells by macrophages, which leads to significantly improved anti‐tumor efficacy in vivo. The findings demonstrate that the concurrent blockade of anti‐phagocytic signals and activation of pro‐phagocytic signals can be effective in macrophage‐mediated cancer immunotherapy.
The phagocytosis of tumor cells by macrophages requires both the coordinated disruption of “don't eat me” signals and simultaneous activation of “eat me” signals. Herein, a nanoparticle‐enabled strategy is proposed to concurrently modulate the cell surface levels of calreticulin (CALR) and CD47 to improve macrophage phagocytosis for improved cancer immunotherapy.
The chronic rejection responses and side effects of the systematic administration of immunosuppressants are the main obstacles to heart allograft and patient survival. The development of ...xenotransplantation also urgently requires more efficient immune regulation strategies. Herein, it is demonstrated that lymph‐node (LN)‐targeted drug delivery can realize LN‐specific immunomodulation with attenuated immune suppression on distant peripheral immune organs to effectively prolong long‐term survival after heart transplantation in a chronic murine heart transplantation model. A chemokine C‐C motif ligand 21 (CCL21) specific aptamer for LN targeting is decorated onto the surface of the hybrid nanoparticular delivery vector mainly composed of CaCO3/CaP/heparin. The targeting delivery system can dramatically enhance accumulation of the loaded immunosuppressant, fingolimod hydrochloride (FTY720), in draining lymph nodes (dLNs) for inducing powerful immune suppression. By promoting the generation of endogenous regulatory T cells (Tregs) and decreasing the proportion of effector T cells (Teffs) in dLNs after heart transplantation, the LN‐targeting strategy can effectively regulate local immune responses instead of systemic immunity, which reduces the incidence of long‐term complications. This study provides an efficient strategy to improve the survival rate after organ transplantation by precise and localized immunoregulation with minimized side effects of immunosuppression.
A targeting drug delivery system decorated by a chemokine C‐C motif ligand 21 (CCL21) specific aptamer can realize lymph‐node‐targeted immunomodulation with attenuated immune suppression on distant peripheral immune organs, resulting in effectively prolonged long‐term survival after heart transplantation. This study provides an efficient strategy to achieve precise and localized immunoregulation with minimized side effects of immunosuppression.
Elastomers with excellent mechanical properties are in substantial demand for various applications, but there is always a tradeoff between their mechanical strength and stretchability. For example, ...partially replacing strong covalent crosslinking by weak sacrificial bonds can enhance the stretchability but also usually decreases the mechanical strength. To surmount this inherent tradeoff, a supramolecular strategy of introducing a zipper‐like sliding‐ring mechanism in a hydrogen‐bond‐crosslinked polyurethane network is proposed. A very small amount (0.5 mol%) of an external additive (pseudo2rotaxane crosslinker) can dramatically increase both the mechanical strength and elongation of this polyurethane network by nearly one order of magnitude. Based on the investigation of the relationship between molecular structure and mechanical properties, this enhancement is attributable to a unique molecular‐level zipper‐like ring‐sliding motion, which efficiently dissipates mechanical work in the solvent‐free network. This research not only provides a distinct and general strategy for the construction of high‐performance elastomers but also paves the way for the practical application of artificial molecular machines toward solvent‐free polyurethane networks.
A molecular zipper elastomer—the combination of ring‐sliding effects and dense hydrogen‐bonding crystal domains in a dry polymer network—results in unexpectedly substantial improvements to the elastomer mechanical performance, including stretchability and strength. The mechanism is found to be the ring‐sliding motion against hydrogen‐bonding domains upon stretching, which effectively dissipates the input mechanical energy.
Background and Purpose
Atherosclerosis induced by cyclosporine A (CsA), an inhibitor of the calcineurin/nuclear factor of activated T cells (NFAT) pathway, is a major concern after organ ...transplantation. However, the atherosclerotic mechanisms of CsA remain obscure. We previously demonstrated that calcineurin/NFAT signalling inhibition contributes to atherogenesis via suppressing microRNA‐204 (miR‐204) transcription. We therefore hypothesised that miR‐204 is involved in the development of CsA‐induced atherosclerosis.
Experimental Approach
ApoE−/− mice with macrophage‐miR‐204 overexpression were generated to determine the effects of miR‐204 on CsA‐induced atherosclerosis. Luciferase reporter assays and chromatin immunoprecipitation sequencing were performed to explore the targets mediating miR‐204 effects.
Key Results
CsA alone did not significantly affect atherosclerotic lesions or serum lipid levels. However, it exacerbated high‐fat diet‐induced atherosclerosis and hyperlipidemia in C57BL/6J and ApoE−/− mice, respectively. miR‐204 levels decreased in circulating monocytes and plaque lesions during CsA‐induced atherosclerosis. The upregulation of miR‐204 in macrophages inhibited CsA‐induced atherosclerotic plaque formation but did not affect serum lipid levels. miR‐204 limited the CsA‐induced foam cell formation by reducing the expression of the scavenger receptors SR‐BII and CD36. SR‐BII was post‐transcriptionally regulated by mature miR‐204‐5p via 3′‐UTR targeting. Additionally, nuclear‐localised miR‐204‐3p prevented the CsA‐induced binding of Ago2 to the CD36 promoter, suppressing CD36 transcription. SR‐BII or CD36 expression restoration dampened the beneficial effects of miR‐204 on CsA‐induced atherosclerosis.
Conclusion and Implications
Macrophage miR‐204 ameliorates CsA‐induced atherosclerosis, suggesting that miR‐204 may be a potential target for the prevention and treatment of CsA‐related atherosclerotic side effects.
Conversion of carbon dioxide (CO2) into valuable chemicals, especially liquid fuels, through electrochemical reduction driven by sustainable energy sources, is a promising way to get rid of ...dependence on fossil fuels, wherein developing of highly efficient catalyst is still of paramount importance. In this study, as a proof‐of‐concept experiment, first a facile while very effective protocol is proposed to synthesize amorphous Cu NPs. Unexpectedly, superior electrochemical performances, including high catalytic activity and selectivity of CO2 reduction to liquid fuels are achieved, that is, a total Faradaic efficiency of liquid fuels can sum up to the maximum value of 59% at −1.4 V, with formic acid (HCOOH) and ethanol (C2H6O) account for 37% and 22%, respectively, as well as a desirable long‐term stability even up to 12 h. More importantly, this work opens a new avenue for improved electroreduction of CO2 based on amorphous metal catalysts.
An amorphous Cu catalyst displays superior catalytic activity toward electroreduction of CO2 with a remarkable selectivity for the reduction to liquid fuels (HCOOH andC2H6O) relative to a crystalline Cu catalyst.
Halide solid electrolytes, known for their high ionic conductivity at room temperature and good oxidative stability, face notable challenges in all–solid–state Li–ion batteries (ASSBs), especially ...with unstable cathode/solid electrolyte (SE) interface and increasing interfacial resistance during cycling. In this work, we have developed an Al3+–doped, cation–disordered epitaxial nanolayer on the LiCoO2 surface by reacting it with an artificially constructed AlPO4 nanoshell; this lithium–deficient layer featuring a rock–salt–like phase effectively suppresses oxidative decomposition of Li3InCl6 electrolyte and stabilizes the cathode/SE interface at 4.5 V. The ASSBs with the halide electrolyte Li3InCl6 and a high–loading LiCoO2 cathode demonstrated high discharge capacity and long cycling life from 3 to 4.5 V. Our findings emphasize the importance of specialized cathode surface modification in preventing SE degradation and achieving stable cycling of halide–based ASSBs at high voltages.
We have demonstrated a surface‐lattice‐doping (SLD) strategy for the stabilization of the solid electrolyte/cathode interface for its working at a high voltage of 4.5 V. Specifically, a uniform AlPO4 coating layer was built with nanometer precision around the LiCoO2 (LCO) particle. The following sintering at high temperature induced a homogeneous Al3+ diffusion into the LCO crust, leading to a controlled degree of surface Al/Co/Li disorder together with the formed Li+‐conductive Li3PO4 islands decorating the LCO surface. We found that this SLD strategy is capable of not only suppressing the structural degradation of LCO itself, but also effectively mitigating the decomposition of the chloride‐based solid electrolyte at the interface, thereby ensuring the assembled all‐solid‐state batteries with the halide electrolyte Li3InCl6 and a LiCoO2 cathode excellent cycling stability at 4.5 V.
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