Monocytes (MC), lymphocytes (LC) and Kupffer cells (KC) were isolated respectively from blood and surgical liver samples of patients suffering from he-patocellular carcinoma (HCC). 13 patients were given BCG, mixed ba...Monocytes (MC), lymphocytes (LC) and Kupffer cells (KC) were isolated respectively from blood and surgical liver samples of patients suffering from he-patocellular carcinoma (HCC). 13 patients were given BCG, mixed bacterium vaccine (MBV) and human white blood cell interferon (IFN), the other 3 patients were not treated with any biological immune stimulants (BIS) and served as controls. The cytosta-tic and cytotoxic effects of MC and KC on human hepatoma SMMC-7721 (TC) were assayed in vitro and the numbers of T total (Tt), T helper (Th) and T suppressor (Ts) cells were counted using CD monoclonal antibody immunofluorescence. The results were as follows: (1) On the 7th day after the first administration of BIS, the cytostatic and cytotoxic effects of MC on TC showed obvious increase over pre-administration. The activity of BIS was 1 ?5 times as high as that in the controls. (2) After 3 administrations, the cytostatic effect of MC on TC increased to the normal level (84%), while the controls remained as before (45%). (3) On the 7th day after first administration, cytostatic and cytotoxic effects of KC on TC were 0.5 and 1 times higher respectively than those of the controls. (4) The numbers of Tt and Th of patients given BIS increased continuously; on the contrary Ts decreased in number. These results indicate that combined use of BCG, MBV and IFN can actively enhance the immune anti-hepatoma function of patients suffering from HCC.展开更多
Cancer immunotherapy has emerged as a promising strategy for the treatment of cancer,with the tumor microenvironment(TME)playing a pivotal role in modulating the immune response.CD47,a cell surface protein,has been id...Cancer immunotherapy has emerged as a promising strategy for the treatment of cancer,with the tumor microenvironment(TME)playing a pivotal role in modulating the immune response.CD47,a cell surface protein,has been identified as a crucial regulator of the TME and a potential therapeutic target for cancer therapy.However,the precise functions and implications of CD47 in the TME during immunotherapy for cancer patients remain incompletely understood.This comprehensive review aims to provide an overview of CD47’s multifaced role in TME regulation and immune evasion,elucidating its impact on various types of immunotherapy outcomes,including checkpoint inhibitors and CAR T-cell therapy.Notably,CD47-targeted therapies offer a promising avenue for improving cancer treatment outcomes,especially when combined with other immunotherapeutic approaches.The review also discusses current and potential CD47-targeted therapies being explored for cancer treatment and delves into the associated challenges and opportunities inherent in targeting CD47.Despite the demonstrated effectiveness of CD47-targeted therapies,there are potential problems,including unintended effects on healthy cells,hematological toxicities,and the development if resistance.Consequently,further research efforts are warranted to fully understand the underlying mechanisms of resistance and to optimize CD47-targeted therapies through innovative combination approaches,ultimately improving cancer treatment outcomes.Overall,this comprehensive review highlights the significance of CD47 as a promising target for cancer immunotherapy and provides valuable insight into the challenges and opportunities in developing effective CD47-targeted therapies for cancer treatment.展开更多
Objective:Patients with non–small cell lung cancer(NSCLC)respond differently to cytokine-induced killer cell(CIK)treatment.Therefore,potential prognostic markers to identify patients who would benefit from CIK treatm...Objective:Patients with non–small cell lung cancer(NSCLC)respond differently to cytokine-induced killer cell(CIK)treatment.Therefore,potential prognostic markers to identify patients who would benefit from CIK treatment must be elucidated.The current research aimed at identifying predictive prognostic markers for efficient CIK treatment of patients with NSCLC.Methods:Patients histologically diagnosed with NSCLC were enrolled from the Tianjin Medical University Cancer Institute and Hospital.We performed whole-exome sequencing(WES)on the tumor tissues and paired adjacent benign tissues collected from 50 patients with NSCLC,and RNA-seq on tumor tissues of 17 patients with NSCLC before CIK immunotherapy treatment.Multivariate Cox proportional hazard regression analysis was used to analyze the association between clinical parameters and prognostic relevance.WES and RNA-seq data between lung squamous cell carcinoma(SCC)and adenocarcinoma(Aden)were analyzed and compared.Results:The pathology subtype of lung cancer was the most significantly relevant clinical parameter associated with DFS,as analyzed by multivariate Cox proportional hazard regression(P=0.031).The patients with lung SCC showed better CIK treatment efficacy and extended DFS after CIK treatment.Relatively low expression of HLA class II genes and checkpoint molecules,and less immunosuppressive immune cell infiltration were identified in the patients with lung SCC.Conclusions:Coordinated suppression of the expression of HLA class II genes and checkpoint molecules,as well as less immune suppressive cell infiltration together contributed to the better CIK treatment efficacy in lung SCC than lung Aden.展开更多
Metastatic renal cell cancer(mRCC)management has undergone a paradigm shift in recent decades.The first revolution came with the emergence of vascular endothelial growth factor inhibitors;there was a second wave with ...Metastatic renal cell cancer(mRCC)management has undergone a paradigm shift in recent decades.The first revolution came with the emergence of vascular endothelial growth factor inhibitors;there was a second wave with the unprecedented success of checkpoint inhibitors,and then the latest approach,which is becoming the new care standard in mRCC,of combining these two strategies in different ways.Updated results of Checkmate-214 after 42 mo of follow-up were consistent with previously published results showing the superiority of nivolumab/ipilimumab over sunitinib in progression free survival(PFS),overall survival(OS),and objective response rate(ORR)in intermediate and high-risk patients.However,several studies presented at the American Society of Clinical Oncology 2020 suggested that the best place,and so far,the only one for nivolumab/ipilimumab is the frontline setting.The update on Keynote-426 after 23 mo of follow-up showed no superiority of pembrolizumab/axitinib over sunitinib in favorable-risk mRCC,suggesting that it should no longer be the first line of choice in low-risk patients.Finally,the phase III Checkmate 9ER trial results revealed the superiority of nivolumab/cabozantinib vs sunitinib in PFS,OS,and ORR,providing a new first-line option among all International Metastatic RCC Database Consortium risk patients.Some phase II clinical trials also presented this year showed promising results with new combination therapies such as nivolumab/sitravatinib,cabozantinib/atezolizumab,and lenvatinib/pembrolizumab,providing promising grounds upon which to start phase III studies.In addition,other works are using novel therapeutic agents with different mechanisms of action,including telaglenastat(a glutaminase inhibitor),entinostat[an inhibitor of histone deacetylases(HDACs)],and olaparib and talazoparib,poly(ADP-ribose)polymerase inhibitors widely used in other tumors.However,some questions regarding mRCC management still need to be addressed,such as head-to-head comparisons between the current options,treatment sequencing,non-clear cell mRCC,and the role of biomarkers to ascertain the best treatment choice.展开更多
Blood mononuclear cells consist of T cells and monocyte derived cells. Beside immunity, the blood mononuclear cells belong to the complex tissue control system(TCS), where they exhibit morphostatic function by stimula...Blood mononuclear cells consist of T cells and monocyte derived cells. Beside immunity, the blood mononuclear cells belong to the complex tissue control system(TCS), where they exhibit morphostatic function by stimulatingproliferation of tissue stem cells followed by cellular differentiation, that is stopped after attaining the proper functional stage, which differs among various tissue types. Therefore, the term immune and morphostatic system(IMS) should be implied. The TCS-mediated morphostasis also consists of vascular pericytes controlled by autonomic innervation, which is regulating the quantity of distinct tissues in vivo. Lack of proper differentiation of tissue cells by TCS causes either tissue underdevelopment, e.g., muscular dystrophy, or degenerative functional failures, e.g., type 1 diabetes and age-associated diseases. With the gradual IMS regression after 35 years of age the gonadal infertility develops, followed by a growing incidence of age-associated diseases and cancers. Without restoring an altered TCS function in a degenerative disease, the implantation of tissue-specific stem cells alone by regenerative medicine can not be successful. Transfused young blood could temporarily restore fertility to enable parenthood. The young blood could also temporarily alleviate aging diseases, and this can be extended by substances inducing IMS regeneration, like the honey bee propolis. The local and/or systemic use of honey bee propolis stopped hair and teeth loss, regressed varicose veins, improved altered hearing, and lowered high blood pressure and sugar levels. Complete regression of stage Ⅳ ovarian cancer with liver metastases after a simple elaborated immunotherapy is also reported.展开更多
The chemokine system consists of four different subclasses with over 50 chemokines and 19 receptors. Their functions in the immune system have been well elucidated and research during the last decades unveils their ne...The chemokine system consists of four different subclasses with over 50 chemokines and 19 receptors. Their functions in the immune system have been well elucidated and research during the last decades unveils their new roles in hepatocellular carcinoma(HCC). The chemokines and their receptors in the microenvironment influence the development of HCCby several aspects including:inflammation,effects on immune cells,angiogenesis,and direct effects on HCC cells. Regarding these aspects,pre-clinical research by targeting the chemokine system has yielded promising data,and these findings bring us new clues in the chemokine-based therapies for HCC.展开更多
Patients infected with the hepatitis C virus(HCV) are characterized by a high incidence of chronic infection, which results in chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. The functional impairmen...Patients infected with the hepatitis C virus(HCV) are characterized by a high incidence of chronic infection, which results in chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. The functional impairment of HCV-specific T cells is associated with the evolution of an acute infection to chronic hepatitis. While T cells are the important effector cells in adaptive immunity, natural killer(NK) cells are the critical effector cells in innate immunity to virus infections. The findings of recent studies on NK cells in hepatitis C suggest that NK cell responses are indeed important in each phase of HCV infection. In the early phase, NK cells are involved in protective immunity to HCV. The immune evasion strategies used by HCV may target NK cells and might contribute to the progression to chronic hepatitis C. NK cells may control HCV replication and modulate hepatic fibrosis in the chronic phase. Further investigations are, however, needed, because a considerable number of studies observed functional impairment of NK cells in chronic HCV infection. Interestingly, the enhanced NK cell responses during interferon-α-based therapy of chronic hepatitis C indicate successful treatment. In spite of the advances in research on NK cells in hepatitis C, establishment of more physiological HCV infection model systems is needed to settle unsolved controversies over the role and functional status of NK cells in HCV infection.展开更多
The relationship of the immune system and tumour cells is complex; although recognised that the immune system can protect the host against tumour development, the immune system also facilitates tumour progression thro...The relationship of the immune system and tumour cells is complex; although recognised that the immune system can protect the host against tumour development, the immune system also facilitates tumour progression through immune suppression. Pro-inflammatory mediators associated with chronic inflammation are responsible for the expansion and activation of myeloid derived suppressor cells(MDSCs); a heterogeneous group of cells that originates from myeloid progenitor cells but does not complete the final stages of differentiation. A causal relationship between chronic inflammation and tumour progression relies on the accumulation and maintenance of MDSCs as its linchpin; responsible for immunosuppression through the down-regulation of antitumour responses. MDSCs cause immunosuppression through a number of mechanisms; inhibiting the proliferation of CD4^+ and CD8^+ T cells, blocking natural killer cell activation and limiting dendritic cell maturation and function. As well as using various mechanisms to inhibit adaptive and immune responses, MDSCs also have non-immunological functions that aid tumour spread; including directly promoting tumour proliferation and metastasis by having an important role in tumour angiogenesis, secretion of matrix metalloproteinases and induction of epithelial-mesenchymal transition. Breast cancer is the most common cancer among women in the United Kingdom with 44540 new cases of invasive carcinoma in 2013 and results in the second highest cancer mortality rate in women, with 11600 deaths in 2012. Considering this, the need for novel therapeutic interventions is higher than ever. This review summarises the rationale for the targeting of MDSCs in breast cancer as a realistic avenue to increase survival from breast cancer.展开更多
文摘Monocytes (MC), lymphocytes (LC) and Kupffer cells (KC) were isolated respectively from blood and surgical liver samples of patients suffering from he-patocellular carcinoma (HCC). 13 patients were given BCG, mixed bacterium vaccine (MBV) and human white blood cell interferon (IFN), the other 3 patients were not treated with any biological immune stimulants (BIS) and served as controls. The cytosta-tic and cytotoxic effects of MC and KC on human hepatoma SMMC-7721 (TC) were assayed in vitro and the numbers of T total (Tt), T helper (Th) and T suppressor (Ts) cells were counted using CD monoclonal antibody immunofluorescence. The results were as follows: (1) On the 7th day after the first administration of BIS, the cytostatic and cytotoxic effects of MC on TC showed obvious increase over pre-administration. The activity of BIS was 1 ?5 times as high as that in the controls. (2) After 3 administrations, the cytostatic effect of MC on TC increased to the normal level (84%), while the controls remained as before (45%). (3) On the 7th day after first administration, cytostatic and cytotoxic effects of KC on TC were 0.5 and 1 times higher respectively than those of the controls. (4) The numbers of Tt and Th of patients given BIS increased continuously; on the contrary Ts decreased in number. These results indicate that combined use of BCG, MBV and IFN can actively enhance the immune anti-hepatoma function of patients suffering from HCC.
基金the Huzhou Science and Technology Bureau,Zhejiang Province,China(2020GZ41).
文摘Cancer immunotherapy has emerged as a promising strategy for the treatment of cancer,with the tumor microenvironment(TME)playing a pivotal role in modulating the immune response.CD47,a cell surface protein,has been identified as a crucial regulator of the TME and a potential therapeutic target for cancer therapy.However,the precise functions and implications of CD47 in the TME during immunotherapy for cancer patients remain incompletely understood.This comprehensive review aims to provide an overview of CD47’s multifaced role in TME regulation and immune evasion,elucidating its impact on various types of immunotherapy outcomes,including checkpoint inhibitors and CAR T-cell therapy.Notably,CD47-targeted therapies offer a promising avenue for improving cancer treatment outcomes,especially when combined with other immunotherapeutic approaches.The review also discusses current and potential CD47-targeted therapies being explored for cancer treatment and delves into the associated challenges and opportunities inherent in targeting CD47.Despite the demonstrated effectiveness of CD47-targeted therapies,there are potential problems,including unintended effects on healthy cells,hematological toxicities,and the development if resistance.Consequently,further research efforts are warranted to fully understand the underlying mechanisms of resistance and to optimize CD47-targeted therapies through innovative combination approaches,ultimately improving cancer treatment outcomes.Overall,this comprehensive review highlights the significance of CD47 as a promising target for cancer immunotherapy and provides valuable insight into the challenges and opportunities in developing effective CD47-targeted therapies for cancer treatment.
基金This work was supported by the National Key Technologies R&D Program(Grant No.2015BAI12B12)the National Key R&D Program(Grant No.2018YFC1313400)+2 种基金grants from the National Natural Science Foundation of China(Grant Nos.81802873 and 81672697)the Natural Science Foundation of Tianjin(Grant No.18JCQNJC81300)the Tianjin Municipal Education Commission Program(Grant No.2017KJ197).
文摘Objective:Patients with non–small cell lung cancer(NSCLC)respond differently to cytokine-induced killer cell(CIK)treatment.Therefore,potential prognostic markers to identify patients who would benefit from CIK treatment must be elucidated.The current research aimed at identifying predictive prognostic markers for efficient CIK treatment of patients with NSCLC.Methods:Patients histologically diagnosed with NSCLC were enrolled from the Tianjin Medical University Cancer Institute and Hospital.We performed whole-exome sequencing(WES)on the tumor tissues and paired adjacent benign tissues collected from 50 patients with NSCLC,and RNA-seq on tumor tissues of 17 patients with NSCLC before CIK immunotherapy treatment.Multivariate Cox proportional hazard regression analysis was used to analyze the association between clinical parameters and prognostic relevance.WES and RNA-seq data between lung squamous cell carcinoma(SCC)and adenocarcinoma(Aden)were analyzed and compared.Results:The pathology subtype of lung cancer was the most significantly relevant clinical parameter associated with DFS,as analyzed by multivariate Cox proportional hazard regression(P=0.031).The patients with lung SCC showed better CIK treatment efficacy and extended DFS after CIK treatment.Relatively low expression of HLA class II genes and checkpoint molecules,and less immunosuppressive immune cell infiltration were identified in the patients with lung SCC.Conclusions:Coordinated suppression of the expression of HLA class II genes and checkpoint molecules,as well as less immune suppressive cell infiltration together contributed to the better CIK treatment efficacy in lung SCC than lung Aden.
文摘Metastatic renal cell cancer(mRCC)management has undergone a paradigm shift in recent decades.The first revolution came with the emergence of vascular endothelial growth factor inhibitors;there was a second wave with the unprecedented success of checkpoint inhibitors,and then the latest approach,which is becoming the new care standard in mRCC,of combining these two strategies in different ways.Updated results of Checkmate-214 after 42 mo of follow-up were consistent with previously published results showing the superiority of nivolumab/ipilimumab over sunitinib in progression free survival(PFS),overall survival(OS),and objective response rate(ORR)in intermediate and high-risk patients.However,several studies presented at the American Society of Clinical Oncology 2020 suggested that the best place,and so far,the only one for nivolumab/ipilimumab is the frontline setting.The update on Keynote-426 after 23 mo of follow-up showed no superiority of pembrolizumab/axitinib over sunitinib in favorable-risk mRCC,suggesting that it should no longer be the first line of choice in low-risk patients.Finally,the phase III Checkmate 9ER trial results revealed the superiority of nivolumab/cabozantinib vs sunitinib in PFS,OS,and ORR,providing a new first-line option among all International Metastatic RCC Database Consortium risk patients.Some phase II clinical trials also presented this year showed promising results with new combination therapies such as nivolumab/sitravatinib,cabozantinib/atezolizumab,and lenvatinib/pembrolizumab,providing promising grounds upon which to start phase III studies.In addition,other works are using novel therapeutic agents with different mechanisms of action,including telaglenastat(a glutaminase inhibitor),entinostat[an inhibitor of histone deacetylases(HDACs)],and olaparib and talazoparib,poly(ADP-ribose)polymerase inhibitors widely used in other tumors.However,some questions regarding mRCC management still need to be addressed,such as head-to-head comparisons between the current options,treatment sequencing,non-clear cell mRCC,and the role of biomarkers to ascertain the best treatment choice.
文摘Blood mononuclear cells consist of T cells and monocyte derived cells. Beside immunity, the blood mononuclear cells belong to the complex tissue control system(TCS), where they exhibit morphostatic function by stimulatingproliferation of tissue stem cells followed by cellular differentiation, that is stopped after attaining the proper functional stage, which differs among various tissue types. Therefore, the term immune and morphostatic system(IMS) should be implied. The TCS-mediated morphostasis also consists of vascular pericytes controlled by autonomic innervation, which is regulating the quantity of distinct tissues in vivo. Lack of proper differentiation of tissue cells by TCS causes either tissue underdevelopment, e.g., muscular dystrophy, or degenerative functional failures, e.g., type 1 diabetes and age-associated diseases. With the gradual IMS regression after 35 years of age the gonadal infertility develops, followed by a growing incidence of age-associated diseases and cancers. Without restoring an altered TCS function in a degenerative disease, the implantation of tissue-specific stem cells alone by regenerative medicine can not be successful. Transfused young blood could temporarily restore fertility to enable parenthood. The young blood could also temporarily alleviate aging diseases, and this can be extended by substances inducing IMS regeneration, like the honey bee propolis. The local and/or systemic use of honey bee propolis stopped hair and teeth loss, regressed varicose veins, improved altered hearing, and lowered high blood pressure and sugar levels. Complete regression of stage Ⅳ ovarian cancer with liver metastases after a simple elaborated immunotherapy is also reported.
基金Supported by National Science Foundation of China,No.31471147
文摘The chemokine system consists of four different subclasses with over 50 chemokines and 19 receptors. Their functions in the immune system have been well elucidated and research during the last decades unveils their new roles in hepatocellular carcinoma(HCC). The chemokines and their receptors in the microenvironment influence the development of HCCby several aspects including:inflammation,effects on immune cells,angiogenesis,and direct effects on HCC cells. Regarding these aspects,pre-clinical research by targeting the chemokine system has yielded promising data,and these findings bring us new clues in the chemokine-based therapies for HCC.
基金Supported by Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of ScienceICT&Future Planning+1 种基金No.2007-0056092No.2012R1A1A1012207 and No.2010-0027945
文摘Patients infected with the hepatitis C virus(HCV) are characterized by a high incidence of chronic infection, which results in chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. The functional impairment of HCV-specific T cells is associated with the evolution of an acute infection to chronic hepatitis. While T cells are the important effector cells in adaptive immunity, natural killer(NK) cells are the critical effector cells in innate immunity to virus infections. The findings of recent studies on NK cells in hepatitis C suggest that NK cell responses are indeed important in each phase of HCV infection. In the early phase, NK cells are involved in protective immunity to HCV. The immune evasion strategies used by HCV may target NK cells and might contribute to the progression to chronic hepatitis C. NK cells may control HCV replication and modulate hepatic fibrosis in the chronic phase. Further investigations are, however, needed, because a considerable number of studies observed functional impairment of NK cells in chronic HCV infection. Interestingly, the enhanced NK cell responses during interferon-α-based therapy of chronic hepatitis C indicate successful treatment. In spite of the advances in research on NK cells in hepatitis C, establishment of more physiological HCV infection model systems is needed to settle unsolved controversies over the role and functional status of NK cells in HCV infection.
文摘The relationship of the immune system and tumour cells is complex; although recognised that the immune system can protect the host against tumour development, the immune system also facilitates tumour progression through immune suppression. Pro-inflammatory mediators associated with chronic inflammation are responsible for the expansion and activation of myeloid derived suppressor cells(MDSCs); a heterogeneous group of cells that originates from myeloid progenitor cells but does not complete the final stages of differentiation. A causal relationship between chronic inflammation and tumour progression relies on the accumulation and maintenance of MDSCs as its linchpin; responsible for immunosuppression through the down-regulation of antitumour responses. MDSCs cause immunosuppression through a number of mechanisms; inhibiting the proliferation of CD4^+ and CD8^+ T cells, blocking natural killer cell activation and limiting dendritic cell maturation and function. As well as using various mechanisms to inhibit adaptive and immune responses, MDSCs also have non-immunological functions that aid tumour spread; including directly promoting tumour proliferation and metastasis by having an important role in tumour angiogenesis, secretion of matrix metalloproteinases and induction of epithelial-mesenchymal transition. Breast cancer is the most common cancer among women in the United Kingdom with 44540 new cases of invasive carcinoma in 2013 and results in the second highest cancer mortality rate in women, with 11600 deaths in 2012. Considering this, the need for novel therapeutic interventions is higher than ever. This review summarises the rationale for the targeting of MDSCs in breast cancer as a realistic avenue to increase survival from breast cancer.
