T细胞受体工程化T细胞(T cell receptor-engineered T cells,TCR-T)是目前肿瘤免疫治疗领域的研究热点之一,从2006年首个临床试验成功至今已经取得了一系列令人鼓舞的成果,但快速发展的同时其在杀伤性、安全性、持久性这三方面仍面临着...T细胞受体工程化T细胞(T cell receptor-engineered T cells,TCR-T)是目前肿瘤免疫治疗领域的研究热点之一,从2006年首个临床试验成功至今已经取得了一系列令人鼓舞的成果,但快速发展的同时其在杀伤性、安全性、持久性这三方面仍面临着许多问题。改善肿瘤免疫微环境,增强TCR-T的趋化、浸润与活化将是提高其杀伤肿瘤作用的关键;新抗原具有高度的肿瘤特异性与免疫原性,是保障治疗安全有效和实现个体化肿瘤免疫治疗的基础;另外,回输低分化的T细胞亚群是产生持久免疫应答的可靠方法。本文将结合当前的研究进展,从以上三个角度阐述TCR-T抗肿瘤治疗的现状与挑战。展开更多
Multiple myeloma(MM),considered an incurable hematological malignancy,is characterized by its clonal evolution of malignant plasma cells.Although the application of autologous stem cell transplantation(ASCT)and the in...Multiple myeloma(MM),considered an incurable hematological malignancy,is characterized by its clonal evolution of malignant plasma cells.Although the application of autologous stem cell transplantation(ASCT)and the introduction of novel agents such as immunomodulatory drugs(IMiDs)and proteasome inhibitors(PIs)have doubled the median overall survival to eight years,relapsed and refractory diseases are still frequent events in the course of MM.To achieve a durable and deep remission,immunotherapy modalities have been developed for relapsed/refractory multiple myeloma(RRMM).Among these approaches,chimeric antigen receptor(CAR)T-cell therapy is the most promising star,based on the results of previous success in B-cell neoplasms.In this immunotherapy,autologous T cells are engineered to express an artificial receptor which targets a tumor-associated antigen and initiates the T-cell killing procedure.Tisagenlecleucel and Axicabtagene,targeting the CD19 antigen,are the two pacesetters of CAR T-cell products.They were approved by the US Food and Drug Administration(FDA)in 2017 for the treatment of acute lymphocytic leukemia(ALL)and diffuse large B-cell lymphoma(DLBCL).Their development enabled unparalleled efficacy in combating hematopoietic neoplasms.In this review article,we summarize six promising candidate antigens in MM that can be targeted by CARs and discuss some noteworthy studies of the safety profile of current CAR T-cell therapy.展开更多
Background:Autophagy dysfunction plays a crucial role in tau accumulation and neurodegeneration in Alzheimer’s disease(AD).This study aimed to investigate whether and how the accumulating tau may in turn affect autop...Background:Autophagy dysfunction plays a crucial role in tau accumulation and neurodegeneration in Alzheimer’s disease(AD).This study aimed to investigate whether and how the accumulating tau may in turn affect autophagy.Methods:The primary hippocampal neurons,N2a and HEK293T cells with tau overexpression were respectively starved and treated with vinblastine to study the effects of tau on the initiating steps of autophagy,which was analysed by Student’s two-tailed t-test.The rapamycin and concanamycin A were employed to inhibit the mammalian target of rapamycin kinase complex 1(mTORC1)activity and the vacuolar H+-ATPase(v-ATPase)activity,respectively,which were analysed by One-way ANOVA with post hoc tests.The Western blotting,co-immunoprecipitation and immunofuorescence staining were conducted to gain insight into the mechanisms underlying the tau effects of mTORC1 signaling alterations,as analysed by Student’s two-tailed t-test or One-way ANOVA with post hoc tests.The autophagosome formation was detected by immunofuorescence staining and transmission electron microscopy.The amino acids(AA)levels were detected by high performance liquid chromatography(HPLC).Results:We observed that overexpressing human full-length wild-type tau to mimic AD-like tau accumulation induced autophagy deficits.Further studies revealed that the increased tau could bind to the prion-related domain of T cell intracellular antigen 1(PRD-TIA1)and this association significantly increased the intercellular level of amino acids(Leucine,P=0.0038;Glutamic acid,P=0.0348;Alanine,P=0.0037;Glycine,P=0.0104),with concordant upregulation of mTORC1 activity[phosphorylated eukaryotic translation initiation factor 4E-binding protein 1(p-4EBP1),P<0.0001;phosphorylated 70 kD ribosomal protein S6 kinase 1(p-p70S6K1),P=0.0001,phosphorylated unc-51-like autophagyactivating kinase 1(p-ULK1),P=0.0015]and inhibition of autophagosome formation[microtubuleassociated protein light chain 3 II(LC3 II),P=0.0073;LC3 puncta,P<0.0001].As expected,this tau-induced展开更多
文摘T细胞受体工程化T细胞(T cell receptor-engineered T cells,TCR-T)是目前肿瘤免疫治疗领域的研究热点之一,从2006年首个临床试验成功至今已经取得了一系列令人鼓舞的成果,但快速发展的同时其在杀伤性、安全性、持久性这三方面仍面临着许多问题。改善肿瘤免疫微环境,增强TCR-T的趋化、浸润与活化将是提高其杀伤肿瘤作用的关键;新抗原具有高度的肿瘤特异性与免疫原性,是保障治疗安全有效和实现个体化肿瘤免疫治疗的基础;另外,回输低分化的T细胞亚群是产生持久免疫应答的可靠方法。本文将结合当前的研究进展,从以上三个角度阐述TCR-T抗肿瘤治疗的现状与挑战。
文摘Multiple myeloma(MM),considered an incurable hematological malignancy,is characterized by its clonal evolution of malignant plasma cells.Although the application of autologous stem cell transplantation(ASCT)and the introduction of novel agents such as immunomodulatory drugs(IMiDs)and proteasome inhibitors(PIs)have doubled the median overall survival to eight years,relapsed and refractory diseases are still frequent events in the course of MM.To achieve a durable and deep remission,immunotherapy modalities have been developed for relapsed/refractory multiple myeloma(RRMM).Among these approaches,chimeric antigen receptor(CAR)T-cell therapy is the most promising star,based on the results of previous success in B-cell neoplasms.In this immunotherapy,autologous T cells are engineered to express an artificial receptor which targets a tumor-associated antigen and initiates the T-cell killing procedure.Tisagenlecleucel and Axicabtagene,targeting the CD19 antigen,are the two pacesetters of CAR T-cell products.They were approved by the US Food and Drug Administration(FDA)in 2017 for the treatment of acute lymphocytic leukemia(ALL)and diffuse large B-cell lymphoma(DLBCL).Their development enabled unparalleled efficacy in combating hematopoietic neoplasms.In this review article,we summarize six promising candidate antigens in MM that can be targeted by CARs and discuss some noteworthy studies of the safety profile of current CAR T-cell therapy.
基金supported by grants from the Natural Science Foundation of China(91949205,31730035,81721005)the Science and Technology Committee of China(2016YFC1305800)+1 种基金the Special Project of Technological Innovation of Hubei Province(2018ACA142)Guangdong Provincial Key S&T Program(2018B030336001)。
文摘Background:Autophagy dysfunction plays a crucial role in tau accumulation and neurodegeneration in Alzheimer’s disease(AD).This study aimed to investigate whether and how the accumulating tau may in turn affect autophagy.Methods:The primary hippocampal neurons,N2a and HEK293T cells with tau overexpression were respectively starved and treated with vinblastine to study the effects of tau on the initiating steps of autophagy,which was analysed by Student’s two-tailed t-test.The rapamycin and concanamycin A were employed to inhibit the mammalian target of rapamycin kinase complex 1(mTORC1)activity and the vacuolar H+-ATPase(v-ATPase)activity,respectively,which were analysed by One-way ANOVA with post hoc tests.The Western blotting,co-immunoprecipitation and immunofuorescence staining were conducted to gain insight into the mechanisms underlying the tau effects of mTORC1 signaling alterations,as analysed by Student’s two-tailed t-test or One-way ANOVA with post hoc tests.The autophagosome formation was detected by immunofuorescence staining and transmission electron microscopy.The amino acids(AA)levels were detected by high performance liquid chromatography(HPLC).Results:We observed that overexpressing human full-length wild-type tau to mimic AD-like tau accumulation induced autophagy deficits.Further studies revealed that the increased tau could bind to the prion-related domain of T cell intracellular antigen 1(PRD-TIA1)and this association significantly increased the intercellular level of amino acids(Leucine,P=0.0038;Glutamic acid,P=0.0348;Alanine,P=0.0037;Glycine,P=0.0104),with concordant upregulation of mTORC1 activity[phosphorylated eukaryotic translation initiation factor 4E-binding protein 1(p-4EBP1),P<0.0001;phosphorylated 70 kD ribosomal protein S6 kinase 1(p-p70S6K1),P=0.0001,phosphorylated unc-51-like autophagyactivating kinase 1(p-ULK1),P=0.0015]and inhibition of autophagosome formation[microtubuleassociated protein light chain 3 II(LC3 II),P=0.0073;LC3 puncta,P<0.0001].As expected,this tau-induced
