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BackgroundCurrent stratification systems for tumor prognostic prediction and immunotherapeutic efficacy evaluation are less satisfying in colorectal cancer (CRC). As infiltrating immune cells in tumor microenvironment (TME) played a key role in tumor progression and responses to immune checkpoint blockade (ICB) therapy, we want to construct an immune-related scoring system with detailed immune profiles to stratify CRC patients.MethodsWe developed a scoring system based on immune-related signatures and validated its ability to predict prognosis and immunotherapeutic outcomes in CRC. CD45+ cells from CRC patients were sorted to investigate detailed immune profiles of the stratification system using mass cytometry. A single-cell RNA sequencing dataset was used to analyze transcriptomic profiles.ResultsWe constructed an immune-related signature score (IRScore) based on 54 recurrence-free survival (RFS)-related immune signatures to stratify CRC patients. We revealed that IRScore was positively correlated with RFS and favorable outcomes in ICB treatment. Moreover, we depicted a detailed immune profile in TME using mass cytometry and identified that CD103+CD39+ T cells, characterized by an exhaustive, cytotoxic and proliferative phenotype, were enriched in CRC patients with high IRScore. As a beneficial immune signature, CD103+CD39+ T cells could predict prognosis and responses to ICB therapy in CRC.ConclusionsAll the analyses above revealed that IRScore could be a valuable tool for predicting prognosis and facilitating the development of new therapeutic strategies in CRC, and CD103+CD39+ T cells were one of defined immune signatures in IRScore, which might be a key factor for antitumor immunity.

Background Propofol is a commonly used anesthetic. However, its effects on glioma growth and recurrence remain largely unknown. Methods The effect of propofol on glioma growth was demonstrated by a series of in vitro and in vivo experiments (spheroidal formation assay, western blotting, and xenograft model). The acyl-biotin exchange method and liquid chromatography-mass spectrometry assays identified palmitoylation proteins mediated by the domain containing the Asp-His-His-Cys family. Western blotting, co-immunoprecipitation, quantitative real-time polymerase chain reaction, co-immunoprecipitation, chromatin immunoprecipitation, and luciferase reporter assays were used to explore the mechanisms of the γ-aminobutyric acid receptor (GABAAR)/Src/ZDHHC5/EZH2 signaling axis in the effects of propofol on glioma stem cells (GSCs). Results We found that treatment with a standard dose of propofol promoted glioma growth in nude mice compared with control or low-dose propofol. Propofol-treated GSCs also led to larger tumor growth in nude mice than did vector-treated tumors. Mechanistically, propofol enhances the stem-like properties of gliomas through GABAAR to increase Src expression, thereby enhancing the palmitoylation of ZDHHC5-mediated EZH2 and Oct4 expression. Conclusion These results demonstrate that propofol may promote glioma growth through the GABAAR-Src-ZDHHC5-EZH2 mechanism and are helpful in guiding the clinical use of propofol to obtain a better patient prognosis after the surgical resection of tumors.

Glioblastoma stem cells (GSCs) are a highly tumorigenic cell subgroup of glioblastoma (GBM). Glycogen synthase kinase 3β (GSK3β) is considered a key hub for promoting malignant phenotypes in GBM. However, the functional relationships between GSK3β and GSCs in GBM are unclear. Here, we found that GSK3β was noted as a substrate for ZDHHC4-mediated palmitoylation at the Cys14 residue, which enhanced GBM temozolomide (TMZ) resistance and GSC self-renewal. Clinically, the expression level of ZDHHC4 was upregulated in GBM, which significantly correlated with tumor grade and poor prognosis. The above phenotypes were based on decreasing p-Ser9 and increasing p-Tyr216 by GSK3β palmitoylation, which further activated the enhancer of the zeste homolog 2 (EZH2)–STAT3 pathway. Notably, STAT3 silencing also inhibited ZDHHC4 expression. This study revealed that GSK3β palmitoylation mediated by ZDHHC4 improved the stemness of TMZ-resistant GBM by activating the EZH2–STAT3 signaling axis, providing a new theoretical basis for further understanding the mechanism of TMZ resistance and recurrence after treatment.

Background Pyroptosis is a programmed cell death mediated by the gasdermin superfamily, accompanied by inflammatory and immune responses. Exogenously activated pyroptosis is still not well characterized in the tumor microenvironment. Furthermore, whether pyroptosis-related genes (PRGs) in lower-grade glioma (LGG) may be used as a biomarker remains unknown. Methods The RNA-Sequencing and clinical data of LGG patients were downloaded from publicly available databases. Bioinformatics approaches were used to analyze the relationship between PRGs and LGG patients’ prognosis, clinicopathological features, and immune status. The NMF algorithm was used to differentiate phenotypes, the LASSO regression model was used to construct prognostic signature, and GSEA was used to analyze biological functions and pathways. The expression of the signature genes was verified using qRT-PCR. In addition, the L1000FWD and CMap tools were utilized to screen potential therapeutic drugs or small molecule compounds and validate their effects in glioma cell lines using CCK-8 and colony formation assays. Results Based on PRGs, we defined two phenotypes with different prognoses. Stepwise regression analysis was carried out to identify the 3 signature genes to construct a pyroptosis-related signature. After that, samples from the training and test cohorts were incorporated into the signature and divided by the median RiskScore value (namely, Risk-H and Risk-L). The signature shows excellent predictive LGG prognostic power in the training and validation cohorts. The prognostic signature accurately stratifies patients according to prognostic differences and has predictive value for immune cell infiltration and immune checkpoint expression. Finally, the inhibitory effect of the small molecule inhibitor fedratinib on the viability and proliferation of various glioma cells was verified using cell biology-related experiments. Conclusion This study developed and validated a novel pyroptosis-related signature, which may assist instruct clinicians to predict the prognosis and immunological status of LGG patients more precisely. Fedratinib was found to be a small molecule inhibitor that significantly inhibits glioma cell viability and proliferation, which provides a new therapeutic strategy for gliomas.