Current state and future of co-inhibitory immune checkpoints for the treatment of glioblastoma

In the interaction between a tumor and the immune system,immune checkpoints play an important role,and in tumor immune escape,co-inhibitory immune checkpoints are important.Immune checkpoint inhibitors(ICIs)can enhance the immune system's killing effect on tumors.To date,impressive progress has been made in a variety of tumor treatments;PD1/PDL1 and CTLA4 inhibitors have been approved for clinical use in some tumors.However,glioblastoma(GBM)still lacks an effective treatment.Recently,a phase III clinical trial using nivolumab to treat recurrent GBM showed no significant improvement in overall survival compared to bevacizumab.Therefore,the use of immune checkpoints in the treatment of GBM still faces many challenges.First,to clarify the mechanism of action,how different immune checkpoints play roles in tumor escape needs to be determined;which biomarkers predict a benefit from ICIs treatment and the therapeutic implications for GBM based on experiences in other tumors also need to be determined.Second,to optimize combination therapies,how different types of immune checkpoints are selected for combined application and whether combinations with targeted agents or other immunotherapies exhibit increased efficacy need to be addressed.All of these concerns require extensive basic research and clinical trials.In this study,we reviewed existing knowledge with respect to the issues mentioned above and the progress made in treatments,summarized the state of ICIs in preclinical studies and clinical trials involving GBM,and speculated on the therapeutic prospects of ICIs in the treatment of GBM.

Glioma-derived ANXA1 suppresses the immune response to TLR3 ligands by promoting an anti-inflammatory tumor microenvironment

A highly immunosuppressive tumor microenvironment(TME)and the presence of the blood‒brain barrier are the two major obstacles to eliciting an effective immune response in patients with high-grade glioma(HGG).Here,we tried to enhance the local innate immune response in relapsed HGG by intracranially injecting poly(I:C)to establish a robust antitumor immune response in this registered clinical trial(NCT03392545).During the follow-up,12/27(44.4%)patients who achieved tumor control concomitant with survival benefit were regarded as responders in our study.We found that the T-cell receptor(TCR)repertoire in the TME was reshaped after poly(I:C)treatment.Based on the RNA-seq analysis of tumor samples,the expression of annexin A1(ANXA1)was significantly upregulated in the tumor cells of nonresponders,which was further validated at the protein level.In vitro and in vivo experiments showed that ANXA1 could induce the production of M2-like macrophages and microglia via its surface receptor formyl peptide receptor 1(FPR1)to establish a Treg cell-driven immunosuppressive TME and suppress the antitumor immune response facilitated by poly(I:C).The ANXA1/FPR1 signaling axis can inhibit the innate immune response of glioma patients by promoting an anti-inflammatory and Treg-driven TME.Moreover,ANXA1 could serve as a reliable predictor of response to poly(I:C),with a notable predictive accuracy rate of 92.3%.In light of these notable findings,this study unveils a new perspective of immunotherapy for gliomas.

Station-keeping control for a stratosphere airship via wind speed prediction approach

Purpose–The purpose of this paper is to improve the control precision of the station-keeping control for a stratosphere airship through the feedforward-feedback PID controller which is designed by the wind speed prediction based on the incremental extreme learning machine(I-ELM).Design/methodology/approach–First of all,the online prediction of wind speed is implemented by the I-ELM with rolling time.Second,the feedforward-feedback PID controller is designed through the position information of the airship and the predicted wind speed.In the end,the one-dimensional dynamic model of the stratosphere airship is built,and the controller is applied in the numerical simulation.Findings–Based on the conducted numerical simulations,some valuable conclusions are obtained.First,through the comparison between the predicted value and true value of the wind speed,the wind speed prediction based on I-ELM is very accurate.Second,the feedforward-feedback PID controller designed in this paper is very effective.Originality/value–This paper is very valuable to the research of a high-accuracy station-keeping control of stratosphere airship.