Background The efficacy of anti-programmed cell death protein 1(PD-1)immunotherapy in various cancers,including gastric cancer(GC),needs to be potentiated by more effective targeting to enhance therapeutic efficacy or...Background The efficacy of anti-programmed cell death protein 1(PD-1)immunotherapy in various cancers,including gastric cancer(GC),needs to be potentiated by more effective targeting to enhance therapeutic efficacy or identifying accurate biomarkers to predict clinical responses.Here,we attempted to identify molecules predicting or/and promoting anti-PD-1 therapeutic response in advanced GC(AGC).Methods The transcriptome of AGC tissues from patients with different clinical responses to anti-PD-1 immunotherapy and GC cells was analyzed by RNA sequencing.The protein and mRNA levels of the major facilitator superfamily domain containing 2A(MFSD2A)in GC cells were assessed via quantitative real-time polymerase chain reaction,Western blotting,and immunohistochemistry.Additionally,the regulation of anti-PD-1 response by MFSD2A was studied in tumor-bearing mice.Cytometry by Time-of-Flight,multiple immunohistochemistry,and flow cytometry assays were used to explore immunological responses.The effects of MFSD2A on lipid metabolism in mice cancer tissue and GC cells was detected by metabolomics.Results Higher expression of MFSD2A in tumor tissues of AGC patients was associated with better response to anti-PD-1 immunotherapy.Moreover,MFSD2A expression was lower in GC tissues compared to adjacent normal tissues,and its expression was inversely correlated with GC stage.The overexpression of MFSD2A in GC cells enhanced the efficacy of anti-PD-1 immunotherapy in vivo by reprogramming the tumor microenvironment(TME),characterized by increased CD8+T cell activation and reduced its exhaustion.MFSD2A inhibited transforming growth factorβ1(TGFβ1)release from GC cells by suppressing cyclooxygenase 2(COX2)-prostaglandin synthesis,which consequently reprogrammed TME to promote anti-tumor T cell activation.Conclusions MFSD2A potentially serves as a predictive biomarker for anti-PD-1 immunotherapy response in AGC patients.MFSD2A may be a promising therapeutic target to potentiate the efficacy of anti-PD-1 immunotherapy by reprogramming the TME to promote T cells activation.展开更多
The functional and structural integrity of the blood-brain barrier is crucial in maintaining homeostasis in the brain microenvironment;however,the molecular mechanisms underlying the formation and function of the bloo...The functional and structural integrity of the blood-brain barrier is crucial in maintaining homeostasis in the brain microenvironment;however,the molecular mechanisms underlying the formation and function of the blood-brain barrier remain poorly understood.The major facilitator superfamily domain containing 2A has been identified as a key regulator of blood-brain barrier function.It plays a critical role in promoting and maintaining the formation and functional stability of the blood-brain barrier,in addition to the transport of lipids,such as docosahexaenoic acid,across the blood-brain barrier.Furthermore,an increasing number of studies have suggested that major facilitator superfamily domain containing 2A is involved in the molecular mechanisms of blood-brain barrier dysfunction in a variety of neurological diseases;however,little is known regarding the mechanisms by which major facilitator superfamily domain containing 2A affects the blood-brain barrier.This paper provides a comprehensive and systematic review of the close relationship between major facilitator superfamily domain containing 2A proteins and the blood-brain barrier,including their basic structures and functions,cross-linking between major facilitator superfamily domain containing 2A and the blood-brain barrier,and the in-depth studies on lipid transport and the regulation of blood-brain barrier permeability.This comprehensive systematic review contributes to an in-depth understanding of the important role of major facilitator superfamily domain containing 2A proteins in maintaining the structure and function of the blood-brain barrier and the research progress to date.This will not only help to elucidate the pathogenesis of neurological diseases,improve the accuracy of laboratory diagnosis,and optimize clinical treatment strategies,but it may also play an important role in prognostic monitoring.In addition,the effects of major facilitator superfamily domain containing 2A on blood-brain barrier leakage in various diseases and the research progress on cross-blood-brain barrier drug delivery are summarized.This review may contribute to the development of new approaches for the treatment of neurological diseases.展开更多
基金the CAMS Innovation Fund for Medical Sciences,Grant/Award Numbers:2022-I2M-2-004,2021-I2M-1-074National Natural Science Foundation of China,Grant/Award Numbers:82001677,82102921,82388201+1 种基金Fundamental Research Funds for the Central Universities,Grant/Award Number:3332021075Jiangsu Innovative and Entrepreneurial Talent Programme,Grant/Award Number:2020-30084。
文摘Background The efficacy of anti-programmed cell death protein 1(PD-1)immunotherapy in various cancers,including gastric cancer(GC),needs to be potentiated by more effective targeting to enhance therapeutic efficacy or identifying accurate biomarkers to predict clinical responses.Here,we attempted to identify molecules predicting or/and promoting anti-PD-1 therapeutic response in advanced GC(AGC).Methods The transcriptome of AGC tissues from patients with different clinical responses to anti-PD-1 immunotherapy and GC cells was analyzed by RNA sequencing.The protein and mRNA levels of the major facilitator superfamily domain containing 2A(MFSD2A)in GC cells were assessed via quantitative real-time polymerase chain reaction,Western blotting,and immunohistochemistry.Additionally,the regulation of anti-PD-1 response by MFSD2A was studied in tumor-bearing mice.Cytometry by Time-of-Flight,multiple immunohistochemistry,and flow cytometry assays were used to explore immunological responses.The effects of MFSD2A on lipid metabolism in mice cancer tissue and GC cells was detected by metabolomics.Results Higher expression of MFSD2A in tumor tissues of AGC patients was associated with better response to anti-PD-1 immunotherapy.Moreover,MFSD2A expression was lower in GC tissues compared to adjacent normal tissues,and its expression was inversely correlated with GC stage.The overexpression of MFSD2A in GC cells enhanced the efficacy of anti-PD-1 immunotherapy in vivo by reprogramming the tumor microenvironment(TME),characterized by increased CD8+T cell activation and reduced its exhaustion.MFSD2A inhibited transforming growth factorβ1(TGFβ1)release from GC cells by suppressing cyclooxygenase 2(COX2)-prostaglandin synthesis,which consequently reprogrammed TME to promote anti-tumor T cell activation.Conclusions MFSD2A potentially serves as a predictive biomarker for anti-PD-1 immunotherapy response in AGC patients.MFSD2A may be a promising therapeutic target to potentiate the efficacy of anti-PD-1 immunotherapy by reprogramming the TME to promote T cells activation.
基金supported by the National Natural Science Foundation of China,No.82104412(to TD)Shaanxi Provincial Key R&D Program,No.2023-YBSF-165(to TD)+1 种基金the Natural Science Foundation of Shaanxi Department of Science and Technology,No.2018JM7022(to FM)Shaanxi Provincial Key Industry Chain Project,No.2021ZDLSF04-11(to PW)。
文摘The functional and structural integrity of the blood-brain barrier is crucial in maintaining homeostasis in the brain microenvironment;however,the molecular mechanisms underlying the formation and function of the blood-brain barrier remain poorly understood.The major facilitator superfamily domain containing 2A has been identified as a key regulator of blood-brain barrier function.It plays a critical role in promoting and maintaining the formation and functional stability of the blood-brain barrier,in addition to the transport of lipids,such as docosahexaenoic acid,across the blood-brain barrier.Furthermore,an increasing number of studies have suggested that major facilitator superfamily domain containing 2A is involved in the molecular mechanisms of blood-brain barrier dysfunction in a variety of neurological diseases;however,little is known regarding the mechanisms by which major facilitator superfamily domain containing 2A affects the blood-brain barrier.This paper provides a comprehensive and systematic review of the close relationship between major facilitator superfamily domain containing 2A proteins and the blood-brain barrier,including their basic structures and functions,cross-linking between major facilitator superfamily domain containing 2A and the blood-brain barrier,and the in-depth studies on lipid transport and the regulation of blood-brain barrier permeability.This comprehensive systematic review contributes to an in-depth understanding of the important role of major facilitator superfamily domain containing 2A proteins in maintaining the structure and function of the blood-brain barrier and the research progress to date.This will not only help to elucidate the pathogenesis of neurological diseases,improve the accuracy of laboratory diagnosis,and optimize clinical treatment strategies,but it may also play an important role in prognostic monitoring.In addition,the effects of major facilitator superfamily domain containing 2A on blood-brain barrier leakage in various diseases and the research progress on cross-blood-brain barrier drug delivery are summarized.This review may contribute to the development of new approaches for the treatment of neurological diseases.
