分子靶向-过继性细胞免疫治疗是分子靶向药物和过继性细胞免疫疗法有机结合的新治疗模式,该模式建立在NK细胞活化性信号通路(NKG2D-NKG2DLs)的生物学特性,尤其是受配体可调控性的理论基础之上。分子靶向药物在其中扮演双重角色,除了药...分子靶向-过继性细胞免疫治疗是分子靶向药物和过继性细胞免疫疗法有机结合的新治疗模式,该模式建立在NK细胞活化性信号通路(NKG2D-NKG2DLs)的生物学特性,尤其是受配体可调控性的理论基础之上。分子靶向药物在其中扮演双重角色,除了药物本身对肿瘤细胞的毒性作用外,还作为"刺激诱导"源,诱导肿瘤细胞表达免疫激活物NKG2DLs(nat-ural killer group 2 member D ligands),与NK细胞表面NKG2D(natural killer group 2 member D)结合,激活NK细胞的杀伤活性。NKG2D与NKG2DLs是NK细胞主要的活化性受、配体,在机体抗肿瘤免疫中起重要作用。NKG2D主要表达于NK、CD8+T、γδT和活化的巨噬细胞,参与适应性及固有性免疫应答。与NKG2D结合的配体(NKG2DLs)广泛低表达于多种肿瘤细胞,而在正常组织细胞几乎未见表达,靶细胞的NKG2DLs表达水平直接关系到免疫效应细胞(NK、DC、CTL细胞等)对其的杀伤活性。NKG2DLs的转录与表达可受多种因素影响,分子靶向药物可以诱导肿瘤细胞高表达NKG2DLs,NK细胞对高表达NKG2DLs的肿瘤细胞有较高杀伤活性,而对正常组织无杀伤作用,具有杀伤靶向性;NKG2DLs的高表达也增强了肿瘤细胞对其他免疫效应细胞的杀伤敏感性,具有良好的应用前景。分子靶向药物联合过继性细胞免疫治疗将使肿瘤患者获得更好的临床疗效,预示了肿瘤生物治疗新的发展方向———分子靶向-过继性细胞免疫治疗新模式的来临。展开更多
Background:Human natural killer(NK)cells have attracted widespread attention as a potential adoptive cell therapy(ACT).However,the therapeutic effects of NK cell infusion in patients with solid tumors are limited.Ther...Background:Human natural killer(NK)cells have attracted widespread attention as a potential adoptive cell therapy(ACT).However,the therapeutic effects of NK cell infusion in patients with solid tumors are limited.There is an urgent need to explore a suitable new treatment plan to overcome weaknesses and support the superior therapeutic activity of NK cells.Methods:In this study,the mechanisms underlying the susceptibility of gastric cancer(GC)cell lines AGS,HGC-27,and NCI-N87 to NK cell-mediated cytotoxicity were explored.Results:Lactic dehydrogenase(LDH)release assays showed that all three GC cell lines were susceptible to the umbilical cord blood NK(UCB-NK)cells,and HGC-27 cells with high CD56 expression were the most sensitive to UCB-NK,followed by NCI-N87 and AGS.When the expression of CD56 in HGC-27 cells decreased,the lytic activity of NK cells in HGC-27 cells was abating.In addition,combining oxaliplatin with NK cells produced additive anti-tumor effects in vitro,which may have resulted from oxaliplatin-induced NK group 2 member D(NKG2DL)upregulation in GC cells.These results of cytotoxicity activity showed that inhibition of CD56 expression might suppress the sensitivity of GC cells to NK cell-mediated cytotoxicity,and upregulation of the expression of NKG2DL on the surface of GC cells by oxaliplatin could enhance the killing sensitivity of NK cells.Conclusion:Collectively,our study provides a deeper theoretical foundation and a better therapeutic strategy for NK cell immunotherapy in the treatment of human GC.展开更多
Objective: To examine the effect of pSer9-GSK-3β on breast cancer and to determine whether the underlying metabolic and immunological mechanism is associated with ROS/eIF2B and natural killer(NK) cells.Methods: We em...Objective: To examine the effect of pSer9-GSK-3β on breast cancer and to determine whether the underlying metabolic and immunological mechanism is associated with ROS/eIF2B and natural killer(NK) cells.Methods: We employed TWS119 to inactivate GSK-3β by phosphorylating Ser9 and explored its effect on breast cancer and NK cells. The expression of GSK-3β, natural killer group 2 member D(NKG2D) ligands, eIF2B was quantified by PCR and Western blot. We measured intracellular reactive oxygen species(ROS) and mitochondrial ROS using DCFH-DA and MitoSOX^(TM) probe,respectively, and conducted quantitative analysis of cellular respiration on 4T1 cells with mitochondrial respiratory chain complex Ⅰ/Ⅲ kits.Results: Our investigation revealed that TWS119 downregulated NKG2D ligands(H60 a and Rae1), suppressed the cytotoxicity of NK cells, and promoted the migration of 4T1 murine breast cancer cells. Nevertheless, LY290042, which attenuates p-GSK-3β formation by inhibiting the PI3K/Akt pathway, reversed these effects. We also found that higher expression of p Ser9-GSK-3β induced higher levels of ROS, and observed that abnormality of mitochondrial respiratory chain complex Ⅰ/Ⅲ function induced the dysfunction of GSK-3β-induced electron transport chain, naturally disturbing the ROS level. In addition, the expression of NOX3 and NOX4 was significantly up-regulated, which affected the generation of ROS and associated with the metastasis of breast cancer. Furthermore, we found that the expression of pSer535-eIF2B promoted the expression of NKG2D ligands(Mult-1 and Rae1) following by expression of pSer9-GSK-3β and generation of ROS.Conclusions: The PI3K/Akt/GSK-3β/ROS/eIF2B pathway could regulate NK cell activity and sensitivity of tumor cells to NK cells,which resulted in breast cancer growth and lung metastasis. Thus, GSK-3β is a promising target of anti-tumor therapy.展开更多
Cancer immunotherapy has been widely recognized as a powerful approach to fight cancers.To date,over 50 phase III trials in cancer immunotherapy are in progress.Among the many immunotherapy approaches,immune checkpoin...Cancer immunotherapy has been widely recognized as a powerful approach to fight cancers.To date,over 50 phase III trials in cancer immunotherapy are in progress.Among the many immunotherapy approaches,immune checkpoint therapy has attracted considerable attention.The reported clinical success of targeting the T cell immune checkpoint receptors PD-1 or CTLA4 by antibodies blockade in advanced stages of cancers has demonstrated the importance of immune modulation.But antibodies-based immunotherapy confronted with some disadvantages,such as immunogenicity,stability,membrane permeability,and production cost.Therefore,alternative approaches including small-molecule-regulated immune response are being introduced.In this review,we focused on some of the key intracellular pathways where small-molecule therapeutic is potential and attractive,which highlights the great potential of natural products in this field.展开更多
文摘分子靶向-过继性细胞免疫治疗是分子靶向药物和过继性细胞免疫疗法有机结合的新治疗模式,该模式建立在NK细胞活化性信号通路(NKG2D-NKG2DLs)的生物学特性,尤其是受配体可调控性的理论基础之上。分子靶向药物在其中扮演双重角色,除了药物本身对肿瘤细胞的毒性作用外,还作为"刺激诱导"源,诱导肿瘤细胞表达免疫激活物NKG2DLs(nat-ural killer group 2 member D ligands),与NK细胞表面NKG2D(natural killer group 2 member D)结合,激活NK细胞的杀伤活性。NKG2D与NKG2DLs是NK细胞主要的活化性受、配体,在机体抗肿瘤免疫中起重要作用。NKG2D主要表达于NK、CD8+T、γδT和活化的巨噬细胞,参与适应性及固有性免疫应答。与NKG2D结合的配体(NKG2DLs)广泛低表达于多种肿瘤细胞,而在正常组织细胞几乎未见表达,靶细胞的NKG2DLs表达水平直接关系到免疫效应细胞(NK、DC、CTL细胞等)对其的杀伤活性。NKG2DLs的转录与表达可受多种因素影响,分子靶向药物可以诱导肿瘤细胞高表达NKG2DLs,NK细胞对高表达NKG2DLs的肿瘤细胞有较高杀伤活性,而对正常组织无杀伤作用,具有杀伤靶向性;NKG2DLs的高表达也增强了肿瘤细胞对其他免疫效应细胞的杀伤敏感性,具有良好的应用前景。分子靶向药物联合过继性细胞免疫治疗将使肿瘤患者获得更好的临床疗效,预示了肿瘤生物治疗新的发展方向———分子靶向-过继性细胞免疫治疗新模式的来临。
基金supported by the CAMS Innovation Fund for Medical Sciences(Grants:2021-I2M-1-070)National Natural Science Foundation of China(Grants 82373767).
文摘Background:Human natural killer(NK)cells have attracted widespread attention as a potential adoptive cell therapy(ACT).However,the therapeutic effects of NK cell infusion in patients with solid tumors are limited.There is an urgent need to explore a suitable new treatment plan to overcome weaknesses and support the superior therapeutic activity of NK cells.Methods:In this study,the mechanisms underlying the susceptibility of gastric cancer(GC)cell lines AGS,HGC-27,and NCI-N87 to NK cell-mediated cytotoxicity were explored.Results:Lactic dehydrogenase(LDH)release assays showed that all three GC cell lines were susceptible to the umbilical cord blood NK(UCB-NK)cells,and HGC-27 cells with high CD56 expression were the most sensitive to UCB-NK,followed by NCI-N87 and AGS.When the expression of CD56 in HGC-27 cells decreased,the lytic activity of NK cells in HGC-27 cells was abating.In addition,combining oxaliplatin with NK cells produced additive anti-tumor effects in vitro,which may have resulted from oxaliplatin-induced NK group 2 member D(NKG2DL)upregulation in GC cells.These results of cytotoxicity activity showed that inhibition of CD56 expression might suppress the sensitivity of GC cells to NK cell-mediated cytotoxicity,and upregulation of the expression of NKG2DL on the surface of GC cells by oxaliplatin could enhance the killing sensitivity of NK cells.Conclusion:Collectively,our study provides a deeper theoretical foundation and a better therapeutic strategy for NK cell immunotherapy in the treatment of human GC.
基金supported by grants from the National Natural Science Foundation of China (Grant No. 8117975 and 31770968)Tianjin Institutes for Basic Sciences (Grant No. 15JCYBJC26900 and 16JCQNJC11700)
文摘Objective: To examine the effect of pSer9-GSK-3β on breast cancer and to determine whether the underlying metabolic and immunological mechanism is associated with ROS/eIF2B and natural killer(NK) cells.Methods: We employed TWS119 to inactivate GSK-3β by phosphorylating Ser9 and explored its effect on breast cancer and NK cells. The expression of GSK-3β, natural killer group 2 member D(NKG2D) ligands, eIF2B was quantified by PCR and Western blot. We measured intracellular reactive oxygen species(ROS) and mitochondrial ROS using DCFH-DA and MitoSOX^(TM) probe,respectively, and conducted quantitative analysis of cellular respiration on 4T1 cells with mitochondrial respiratory chain complex Ⅰ/Ⅲ kits.Results: Our investigation revealed that TWS119 downregulated NKG2D ligands(H60 a and Rae1), suppressed the cytotoxicity of NK cells, and promoted the migration of 4T1 murine breast cancer cells. Nevertheless, LY290042, which attenuates p-GSK-3β formation by inhibiting the PI3K/Akt pathway, reversed these effects. We also found that higher expression of p Ser9-GSK-3β induced higher levels of ROS, and observed that abnormality of mitochondrial respiratory chain complex Ⅰ/Ⅲ function induced the dysfunction of GSK-3β-induced electron transport chain, naturally disturbing the ROS level. In addition, the expression of NOX3 and NOX4 was significantly up-regulated, which affected the generation of ROS and associated with the metastasis of breast cancer. Furthermore, we found that the expression of pSer535-eIF2B promoted the expression of NKG2D ligands(Mult-1 and Rae1) following by expression of pSer9-GSK-3β and generation of ROS.Conclusions: The PI3K/Akt/GSK-3β/ROS/eIF2B pathway could regulate NK cell activity and sensitivity of tumor cells to NK cells,which resulted in breast cancer growth and lung metastasis. Thus, GSK-3β is a promising target of anti-tumor therapy.
基金supported financially by the funding of Exploitation and Utilization of Abundant Natural Products from Plants from Kunming Institute of Botany(KIB2017009)the National Natural Science Foundation of China(U1402227)+2 种基金the 100 Talents Program of the Chinese Academy of Sciences(Y.Li)the Program of Recruited Top Talent of Sciences and Technology of Yunnan Province(2009CI120)the Independent Program of Key Laboratory of Natural Pharmaceutical Chemistry of Yunnan Province(Y.Li).
文摘Cancer immunotherapy has been widely recognized as a powerful approach to fight cancers.To date,over 50 phase III trials in cancer immunotherapy are in progress.Among the many immunotherapy approaches,immune checkpoint therapy has attracted considerable attention.The reported clinical success of targeting the T cell immune checkpoint receptors PD-1 or CTLA4 by antibodies blockade in advanced stages of cancers has demonstrated the importance of immune modulation.But antibodies-based immunotherapy confronted with some disadvantages,such as immunogenicity,stability,membrane permeability,and production cost.Therefore,alternative approaches including small-molecule-regulated immune response are being introduced.In this review,we focused on some of the key intracellular pathways where small-molecule therapeutic is potential and attractive,which highlights the great potential of natural products in this field.
