Immunotherapy has revolutionized cancer treatment and rejuvenated the field of tumor immunology.Several types of immunotherapy,including adoptive cell transfer(ACT)and immune checkpoint inhibitors(ICIs),have obtained ...Immunotherapy has revolutionized cancer treatment and rejuvenated the field of tumor immunology.Several types of immunotherapy,including adoptive cell transfer(ACT)and immune checkpoint inhibitors(ICIs),have obtained durable clinical responses,but their efficacies vary,and only subsets of cancer patients can benefit from them.Immune infiltrates in the tumor microenvironment(TME)have been shown to play a key role in tumor development and will affect the clinical outcomes of cancer patients.Comprehensive profiling of tumor-infiltrating immune cells would shed light on the mechanisms of cancer–immune evasion,thus providing opportunities for the development of novel therapeutic strategies.However,the highly heterogeneous and dynamic nature of the TME impedes the precise dissection of intratumoral immune cells.With recent advances in single-cell technologies such as single-cell RNA sequencing(scRNA-seq)and mass cytometry,systematic interrogation of the TME is feasible and will provide insights into the functional diversities of tumor-infiltrating immune cells.In this review,we outline the recent progress in cancer immunotherapy,particularly by focusing on landmark studies and the recent single-cell characterization of tumor-associated immune cells,and we summarize the phenotypic diversities of intratumoral immune cells and their connections with cancer immunotherapy.We believe such a review could strengthen our understanding of the progress in cancer immunotherapy,facilitate the elucidation of immune cell modulation in tumor progression,and thus guide the development of novel immunotherapies for cancer treatment.展开更多
AIM: To characterize the anticancer function of cytokine-induced killer cells (CIK) and develop an adoptive immunotherapy for the patients with primary hepatocellular carcinoma (HCC), we evaluated the proliferation ra...AIM: To characterize the anticancer function of cytokine-induced killer cells (CIK) and develop an adoptive immunotherapy for the patients with primary hepatocellular carcinoma (HCC), we evaluated the proliferation rate, phenotype and the antitumor activity of human CIK cells from healthy donors and HCC patients in vitro and in vivo. METHODS: Peripheral blood mononuclear cells (PBMC) from healthy donors and patients with primary HCC were incubated in vitro and induced into CIK cells in the presence of various cytokines such as interferon-gamma (IFN-gamma), interleukin-1 (IL-1), IL-2 and monoclonal antibody (mAb) against CD3. The phenotype and characterization of CIK cells were identified by flow cytometric analysis. The cytotoxicity of CIK cells was determined by (51)Cr release assay. RESULTS: The CIK cells were shown to be a heterogeneous population with different cellular phenotypes. The percentage of CD3+/CD56+ positive cells, the dominant effector cells, in total CIK cells from healthy donors and HCC patients, significantly increased from 0.1-0.13% at day 0 to 19.0-20.5% at day 21 incubation, which suggested that the CD3+ CD56+ positive cells proliferated faster than other cell populations of CIK cells in the protocol used in this study. After 28 day in vitro incubation, the CIK cells from patients with HCC and healthy donors increased by more than 300-fold and 500-fold in proliferation cell number, respectively. CIK cells originated from HCC patients possessed a higher in vitro antitumor cytotoxic activity on autologous HCC cells than the autologous lymphokine-activated killer (LAK) cells and PBMC cells. In in vivo animal experiment, CIK cells had stronger effects on the inhibition of tumor growth in Balb/c nude mice bearing BEL-7402-producing tumor than LAK cells (mean inhibitory rate, 84.7% vs 52.8%, P【0.05) or PBMC (mean inhibitory rate, 84.7% vs 37.1%, P【0.01). CONCLUSION: Autologous CIK cells are of highly efficient cytotoxic effector cells against primary hepatocellular carcinoma cells and might 展开更多
Immune-based therapies such as immune checkpoint inhibitors have revolutionized the systemic treatment of various cancer types.The therapeutic application of monoclonal antibodies targeting inhibitory pathways such as...Immune-based therapies such as immune checkpoint inhibitors have revolutionized the systemic treatment of various cancer types.The therapeutic application of monoclonal antibodies targeting inhibitory pathways such as programmed cell death-1(PD-1)/programmed cell death ligand 1(PD-L1)and CTLA-4 to cells of the adaptive immune system has recently been shown to generate meaningful improvement in the clinical outcome of hepatocellular carcinoma(HCC).Nevertheless,current immunotherapeutic approaches induce durable responses in only a subset of HCC patients.Since immunologic mechanisms such as chronic inflammation due to chronic viral hepatitis or alcoholic and nonalcoholic fatty liver disease play a crucial role in the initiation,development,and progression of HCC,it is important to understand the underlying mechanisms shaping the unique tumor microenvironment of liver cancer.The liver is an immunologic organ with large populations of innate and innate-like immune cells and is exposed to bacterial,viral,and fungal antigens through the gut-liver axis.Here,we summarize and highlight the role of these cells in liver cancer and propose strategies to therapeutically target them.We also discuss current immunotherapeutic strategies in HCC and outline recent advances in our understanding of how the therapeutic potential of these agents might be enhanced.展开更多
The immune checkpoint blockade therapy has profoundly revolutionized the field of cancer immunotherapy. However, despite great promise for a variety of cancers, the efficacy of immune checkpoint inhibitors is still lo...The immune checkpoint blockade therapy has profoundly revolutionized the field of cancer immunotherapy. However, despite great promise for a variety of cancers, the efficacy of immune checkpoint inhibitors is still low in colorectal cancer(CRC). This is mainly due to the immunosuppressive feature of the tumor microenvironment(TME). Emerging evidence reveals that certain chemotherapeutic drugs induce immunogenic cell death(ICD), demonstrating great potential for remodeling the immunosuppressive TME. In this study, the potential of ginsenoside Rg3(Rg3) as an ICD inducer against CRC cells was confirmed using in vitro and in vivo experimental approaches. The ICD efficacy of Rg3 could be significantly enhanced by quercetin(QTN) that elicited reactive oxygen species(ROS). To amelioratein vivo delivery barriers associated with chemotherapeutic drugs, a folate(FA)-targeted polyethylene glycol(PEG)-modified amphiphilic cyclodextrin nanoparticle(NP) was developed for co-encapsulation of Rg3 and QTN. The resultant nanoformulation(CD-PEG-FA.Rg3.QTN) significantly prolonged blood circulation and enhanced tumor targeting in an orthotopic CRC mouse model, resulting in the conversion of immunosuppressive TME. Furthermore, the CD-PEG-FA.Rg3.QTN achieved significantly longer survival of animals in combination with Anti-PD-L1. The study provides a promising strategy for the treatment of CRC.展开更多
Background: Chimeric antigen receptor-engineered T-cell(CAR-T) therapy is a newly developed immunotherapy used in the treatment of cancers. Because CAR-T therapy has shown great success in treating CD19-positive hemat...Background: Chimeric antigen receptor-engineered T-cell(CAR-T) therapy is a newly developed immunotherapy used in the treatment of cancers. Because CAR-T therapy has shown great success in treating CD19-positive hematological malignancies, its application has been explored in the treatment of solid tumors, such as liver cancer. In this review, we discuss the immune characteristics of liver cancer, the obstacles encountered during the application of CAR-T therapy, and preclinical and clinical progress in the use of CAR-T therapy in patients with liver cancer.Data sources: The data on CAR-T therapy related to liver cancers were collected by searching Pub Med and the Web of Science databases prior to December 2017 with the keywords "chimeric antigen receptor","CAR-T", "liver cancer", "hepatocellular carcinoma", and "solid tumor". Additional articles were identified by manual search of references found in the primary articles. The data for clinical trials were collected by searching Clinical Trials.gov.Results: The liver has a tolerogenic nature in the intrahepatic milieu and its tumor microenvironment significantly affects tumor progression. The obstacles that reduce the efficacy of CAR-T therapy in solid tumors include a lack of specific tumor antigens, limited trafficking and penetration of CAR-T cells to tumor sites, and an immunosuppressive tumor microenvironment. To overcome these obstacles, several strategies have emerged. In addition, several strategies have been developed to manage the side effects of CAR-T, including enhancing the selectivity of CARs and controlling CAR-T activity. To date, no clinical trials of CAR-T therapy against HCC have been completed. However, preclinical studies in vitro and in vivo have shown potent antitumor efficacy. Glypican-3, mucin-1, epithelial cell adhesion molecule, carcinoembryonic antigen, and other targets are currently being studied.Conclusions: The application of CAR-T therapy for liver cancer is just beginning to be explored and more research is needed. However, we ar展开更多
Cancer immunotherapy has significantly flourished and revolutionized the limited conventional tumor therapies,on account of its good safety and long-term memory ability.Discouragingly,low patient response rates and po...Cancer immunotherapy has significantly flourished and revolutionized the limited conventional tumor therapies,on account of its good safety and long-term memory ability.Discouragingly,low patient response rates and potential immune-related side effects make it rather challenging to literally bring immunotherapy from bench to bedside.However,it has become evident that,although the immunosuppressive tumor microenvironment(TME)plays a pivotal role in facilitating tumor progression and metastasis,it also provides various potential targets for remodeling the immunosuppressive TME,which can consequently bolster the effectiveness of antitumor response and tumor suppression.Additionally,the particular characteristics of TME,in turn,can be exploited as avenues for designing diverse precise targeting nanomedicines.In general,it is of urgent necessity to deliver nanomedicines for remodeling the immunosuppressive TME,thus improving the therapeutic outcomes and clinical translation prospects of immunotherapy.Herein,we will illustrate several formation mechanisms of immunosuppressive TME.More importantly,a variety of strategies concerning remodeling immunosuppressive TME and strengthening patients'immune systems,will be reviewed.Ultimately,we will discuss the existing obstacles and future perspectives in the development of antitumor immunotherapy.Hopefully,the thriving bloom of immunotherapy will bring vibrancy to further exploration of comprehensive cancer treatment.展开更多
Colorectal cancer(CRC)is a predominant life-threatening cancer,with liver and peritoneal metastases as the primary causes of death.Intestinal inflammation,a known CRC risk factor,nurtures a local inflammatory environ...Colorectal cancer(CRC)is a predominant life-threatening cancer,with liver and peritoneal metastases as the primary causes of death.Intestinal inflammation,a known CRC risk factor,nurtures a local inflammatory environment enriched with tumor cells,endothelial cells,immune cells,cancer-associated fibroblasts,immunosuppressive cells,and secretory growth factors.The complex interactions of aberrantly expressed cytokines,chemokines,growth factors,and matrix-remodeling enzymes promote CRC pathogenesis and evoke systemic responses that affect disease outcomes.Mounting evidence suggests that these cytokines and chemokines play a role in the progression of CRC through immunosuppression and modulation of the tumor microenvironment,which is partly achieved by the recruitment of immunosuppressive cells.These cells impart features such as cancer stem cell-like properties,drug resistance,invasion,and formation of the premetastatic niche in distant organs,promoting metastasis and aggressive CRC growth.A deeper understanding of the cytokineand chemokine-mediated signaling networks that link tumor progression and metastasis will provide insights into the mechanistic details of disease aggressiveness and facilitate the development of novel therapeutics for CRC.Here,we summarized the current knowledge of cytokine-and chemokine-mediated crosstalk in the inflammatory tumor microenvironment,which drives immunosuppression,resistance to therapeutics,and metastasis during CRC progression.We also outlined the potential of this crosstalk as a novel therapeutic target for CRC.The major cytokine/chemokine pathways involved in cancer immunotherapy are also discussed in this review.展开更多
Programmed cell death 1（PD-1）/programmed cell death 1 ligand（PD-L1） blockade has shown promising effects in cancer immunotherapy. Removing the so-called ＂brakes＂ on T cell immune responses by blocking the PD-1/P...Programmed cell death 1（PD-1）/programmed cell death 1 ligand（PD-L1） blockade has shown promising effects in cancer immunotherapy. Removing the so-called ＂brakes＂ on T cell immune responses by blocking the PD-1/PDL1 check point should boost anti-tumor immunity and provide durable tumor regression for cancer patients.However, 30%–60% of patients show no response to PD-1/PD-L1 blockade. Thus, it is urgent to explore the underlying resistance mechanisms to improve sensitivity to anti-PD-1/PD-L1 therapy. We propose that the mechanisms promoting resistance mainly include T cell exclusion or exhaustion at the tumor site,immunosuppressive factors in the tumor microenvironment（TME）, and a range of tumor-intrinsic factors. This review highlights the power of studying the cellular and molecular mechanisms of resistance to improve the rational design of combination therapeutic strategies that can be translated to the clinic. Here, we briefly discuss the development of PD-1/PD-L1 blockade agents and focus on the current issues and future prospects for potential combinatorial therapeutic strategies that include anti-PD-1/PD-L1 therapy, based upon the available preclinical and clinical data.展开更多
Genomic instability remains an enabling feature of cancer and promotes malignant transformation.Alterations of DNA damage response(DDR)pathways allow genomic instability,generate neoantigens,upregulate the expression ...Genomic instability remains an enabling feature of cancer and promotes malignant transformation.Alterations of DNA damage response(DDR)pathways allow genomic instability,generate neoantigens,upregulate the expression of programmed death ligand 1(PD-L1)and interact with signaling such as cyclic GMPe AMP synthase-stimulator of interferon genes(cGASe STING)signaling.Here,we review the basic knowledge of DDR pathways,mechanisms of genomic instability induced by DDR alterations,impacts of DDR alterations on immune system,and the potential applications of DDR alterations as biomarkers and therapeutic targets in cancer immunotherapy.展开更多
Cancer immunotherapy has veered the paradigm of cancer treatment.Despite recent advances in immunotherapy for improved antitumor efficacy,the complicated tumor microenvironment(TME)is highly immunosuppressive,yielding...Cancer immunotherapy has veered the paradigm of cancer treatment.Despite recent advances in immunotherapy for improved antitumor efficacy,the complicated tumor microenvironment(TME)is highly immunosuppressive,yielding both astounding and unsatisfactory clinical successes.In this regard,clinical outcomes of currently available immunotherapy are confined to the varied immune systems owing in large part to the lack of understanding of the complexity and diversity of the immune context of the TME.Various advanced designs of nanomedicines could still not fully surmount the delivery barriers of the TME.The immunosuppressive TME may even dampen the efficacy of antitumor immunity.Recently,some nanotechnology-related strategies have been inaugurated to modulate the immunosuppressive cells within the tumor immune microenvironment(TIME)for robust immunotherapeutic responses.In this review,we will highlight the current understanding of the immunosuppressive TIME and identify disparate subclasses of TIME that possess an impact on immunotherapy,especially those unique classes associated with the immunosuppressive effect.The immunoregulatory cell types inside the immunosuppressive TIME will be delineated along with the existing and potential approaches for immunosuppressive cell modulation.After introducing the various strategies,we will ultimately outline both the novel therapeutic targets and the potential issues that affect the efficacy of TIME-based nanomedicines.展开更多
Non-small cell lung cancer(NSCLC) accounts for 80%-85% of all lung malignancies and good diagnosis and prognosis of NSCLC are critical to the increase of its survival rate. Tumor-associated macrophages(TAM) abundantly...Non-small cell lung cancer(NSCLC) accounts for 80%-85% of all lung malignancies and good diagnosis and prognosis of NSCLC are critical to the increase of its survival rate. Tumor-associated macrophages(TAM) abundantly present in numerous cancer types, and the role of TAMs in tumor biology and their prognostic value in cancer become major topics of interest. After various stimulations in the tumor microenvironment, TAMs develop into a M1(tumor-inhibitory) phenotype or M2(tumor-promoting) phenotype. Recent studies show that traditional Chinese medicine(TCM) monomers have markedly inhibitory actions for NSCLC through M1/M2 modulation. Due to the TCM monomers mainly covered five categories, i.e. terpenoids, flavonoids, polysaccharides, natural polyphenols, and alkaloids. Thus, we will discuss the regulation of TCM monomers on TAM involve in these five parts in this review. In addition, the potential role of TAMs as therapeutic targets will be discussed.展开更多
AIM:To investigate whether tumor debris created by high-intensity focused ultrasound(HIFU)could trigger antitumor immunity in a mouse hepatocellular carcinoma model. METHODS:Twenty C57BL/6J mice bearing H22 hepatocell...AIM:To investigate whether tumor debris created by high-intensity focused ultrasound(HIFU)could trigger antitumor immunity in a mouse hepatocellular carcinoma model. METHODS:Twenty C57BL/6J mice bearing H22 hepatocellular carcinoma were used to generate antitumor vaccines.Ten mice underwent HIFU ablation,and the remaining 10 mice received a sham-HIFU procedure with no ultrasound irradiation.Sixty normal mice were randomly divided into HIFU vaccine,tumor vaccine and control groups.These mice were immunized with HIFU-generated vaccine,tumor-generated vaccine,and saline,respectively.In addition,20 mice bearing H22 tumors were successfully treated with HIFU ablation. The protective immunity of the vaccinated mice was investigated before and after a subsequent H22 tumor challenge.Using the 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide assay,the cytotoxicity of splenic lymphocytes co-cultured with H22 cells wasdetermined in vitro before the tumor challenge,and tumor volume and survival were measured in vivo after the challenge in each group.The mechanism was also explored by loading the vaccines with bone marrowderived dendritic cells(DCs). RESULTS:Compared to the control,HIFU therapy, tumor-generated and HIFU-generated vaccines significantly increased cytolytic activity against H22 cells in the splenocytes of the vaccinated mice(P<0.001). The tumor volume was significantly smaller in the HIFU vaccine group than in the tumor vaccine group(P <0.05)and control group(P<0.01).However,there was no tumor growth after H22 rechallenge in the HIFU therapy group.Forty-eight-day survival rate was 100%in mice in the HIFU therapy group,30%in both the HIFU vaccine and tumor vaccine groups,and 20% in the control group,indicating that the HIFU-treated mice displayed significantly longer survival than the vaccinated mice in the remaining three groups(P< 0.001).After bone marrow-derived DCs were incubated with HIFU-generated and tumor-generated vaccines, the number of mature DCs expressing MHC-Ⅱ + ,CD80 + and CD86 + mo展开更多
基金This work was supported by grants from the Beijing Advanced Innovation Center for Genomics at Peking University,Key Technologies R&D Program(2016YFC0900100 and 2016YFC0902300)the National Natural Science Foundation of China(31530036 and 91742203).
文摘Immunotherapy has revolutionized cancer treatment and rejuvenated the field of tumor immunology.Several types of immunotherapy,including adoptive cell transfer(ACT)and immune checkpoint inhibitors(ICIs),have obtained durable clinical responses,but their efficacies vary,and only subsets of cancer patients can benefit from them.Immune infiltrates in the tumor microenvironment(TME)have been shown to play a key role in tumor development and will affect the clinical outcomes of cancer patients.Comprehensive profiling of tumor-infiltrating immune cells would shed light on the mechanisms of cancer–immune evasion,thus providing opportunities for the development of novel therapeutic strategies.However,the highly heterogeneous and dynamic nature of the TME impedes the precise dissection of intratumoral immune cells.With recent advances in single-cell technologies such as single-cell RNA sequencing(scRNA-seq)and mass cytometry,systematic interrogation of the TME is feasible and will provide insights into the functional diversities of tumor-infiltrating immune cells.In this review,we outline the recent progress in cancer immunotherapy,particularly by focusing on landmark studies and the recent single-cell characterization of tumor-associated immune cells,and we summarize the phenotypic diversities of intratumoral immune cells and their connections with cancer immunotherapy.We believe such a review could strengthen our understanding of the progress in cancer immunotherapy,facilitate the elucidation of immune cell modulation in tumor progression,and thus guide the development of novel immunotherapies for cancer treatment.
基金Science and Technology Development Foundation of Beijing Institute of Infectious Diseases,No.01 Z094
文摘AIM: To characterize the anticancer function of cytokine-induced killer cells (CIK) and develop an adoptive immunotherapy for the patients with primary hepatocellular carcinoma (HCC), we evaluated the proliferation rate, phenotype and the antitumor activity of human CIK cells from healthy donors and HCC patients in vitro and in vivo. METHODS: Peripheral blood mononuclear cells (PBMC) from healthy donors and patients with primary HCC were incubated in vitro and induced into CIK cells in the presence of various cytokines such as interferon-gamma (IFN-gamma), interleukin-1 (IL-1), IL-2 and monoclonal antibody (mAb) against CD3. The phenotype and characterization of CIK cells were identified by flow cytometric analysis. The cytotoxicity of CIK cells was determined by (51)Cr release assay. RESULTS: The CIK cells were shown to be a heterogeneous population with different cellular phenotypes. The percentage of CD3+/CD56+ positive cells, the dominant effector cells, in total CIK cells from healthy donors and HCC patients, significantly increased from 0.1-0.13% at day 0 to 19.0-20.5% at day 21 incubation, which suggested that the CD3+ CD56+ positive cells proliferated faster than other cell populations of CIK cells in the protocol used in this study. After 28 day in vitro incubation, the CIK cells from patients with HCC and healthy donors increased by more than 300-fold and 500-fold in proliferation cell number, respectively. CIK cells originated from HCC patients possessed a higher in vitro antitumor cytotoxic activity on autologous HCC cells than the autologous lymphokine-activated killer (LAK) cells and PBMC cells. In in vivo animal experiment, CIK cells had stronger effects on the inhibition of tumor growth in Balb/c nude mice bearing BEL-7402-producing tumor than LAK cells (mean inhibitory rate, 84.7% vs 52.8%, P【0.05) or PBMC (mean inhibitory rate, 84.7% vs 37.1%, P【0.01). CONCLUSION: Autologous CIK cells are of highly efficient cytotoxic effector cells against primary hepatocellular carcinoma cells and might
基金supported by the Intramural Research Program of the NIH,NCI(ZIA BC 011345).
文摘Immune-based therapies such as immune checkpoint inhibitors have revolutionized the systemic treatment of various cancer types.The therapeutic application of monoclonal antibodies targeting inhibitory pathways such as programmed cell death-1(PD-1)/programmed cell death ligand 1(PD-L1)and CTLA-4 to cells of the adaptive immune system has recently been shown to generate meaningful improvement in the clinical outcome of hepatocellular carcinoma(HCC).Nevertheless,current immunotherapeutic approaches induce durable responses in only a subset of HCC patients.Since immunologic mechanisms such as chronic inflammation due to chronic viral hepatitis or alcoholic and nonalcoholic fatty liver disease play a crucial role in the initiation,development,and progression of HCC,it is important to understand the underlying mechanisms shaping the unique tumor microenvironment of liver cancer.The liver is an immunologic organ with large populations of innate and innate-like immune cells and is exposed to bacterial,viral,and fungal antigens through the gut-liver axis.Here,we summarize and highlight the role of these cells in liver cancer and propose strategies to therapeutically target them.We also discuss current immunotherapeutic strategies in HCC and outline recent advances in our understanding of how the therapeutic potential of these agents might be enhanced.
基金financial support from the Department of Education of Jilin Province,China(JJKH20190099KJ)the Outstanding Youth Foundation from the Department of Science and Technology of Jilin Province,China(20170520046JH)+6 种基金Health Commission of Jilin Province,China(2020Q012)Fundamental Research Funds for the Central Universities(China)Talents Cultivation Program of Jilin Universityfinancial support from National Natural Science Foundation of China(81774240,82074154)Siming Scholar from Shanghai Shuguang Hospital(SGXZ-201904,China)financial support from Science Foundation Ireland co-funded under the European Regional Development:Centre for Research in Medical Devices,CURAM(13/RC/2073,Ireland)Synthesis and Solid State Cluster,SSPC(12/RC/2275,Ireland),and Centre for Advanced Materials and Bio Engineering Research,AMBER(12/RC/2275,Ireland)。
文摘The immune checkpoint blockade therapy has profoundly revolutionized the field of cancer immunotherapy. However, despite great promise for a variety of cancers, the efficacy of immune checkpoint inhibitors is still low in colorectal cancer(CRC). This is mainly due to the immunosuppressive feature of the tumor microenvironment(TME). Emerging evidence reveals that certain chemotherapeutic drugs induce immunogenic cell death(ICD), demonstrating great potential for remodeling the immunosuppressive TME. In this study, the potential of ginsenoside Rg3(Rg3) as an ICD inducer against CRC cells was confirmed using in vitro and in vivo experimental approaches. The ICD efficacy of Rg3 could be significantly enhanced by quercetin(QTN) that elicited reactive oxygen species(ROS). To amelioratein vivo delivery barriers associated with chemotherapeutic drugs, a folate(FA)-targeted polyethylene glycol(PEG)-modified amphiphilic cyclodextrin nanoparticle(NP) was developed for co-encapsulation of Rg3 and QTN. The resultant nanoformulation(CD-PEG-FA.Rg3.QTN) significantly prolonged blood circulation and enhanced tumor targeting in an orthotopic CRC mouse model, resulting in the conversion of immunosuppressive TME. Furthermore, the CD-PEG-FA.Rg3.QTN achieved significantly longer survival of animals in combination with Anti-PD-L1. The study provides a promising strategy for the treatment of CRC.
文摘Background: Chimeric antigen receptor-engineered T-cell(CAR-T) therapy is a newly developed immunotherapy used in the treatment of cancers. Because CAR-T therapy has shown great success in treating CD19-positive hematological malignancies, its application has been explored in the treatment of solid tumors, such as liver cancer. In this review, we discuss the immune characteristics of liver cancer, the obstacles encountered during the application of CAR-T therapy, and preclinical and clinical progress in the use of CAR-T therapy in patients with liver cancer.Data sources: The data on CAR-T therapy related to liver cancers were collected by searching Pub Med and the Web of Science databases prior to December 2017 with the keywords "chimeric antigen receptor","CAR-T", "liver cancer", "hepatocellular carcinoma", and "solid tumor". Additional articles were identified by manual search of references found in the primary articles. The data for clinical trials were collected by searching Clinical Trials.gov.Results: The liver has a tolerogenic nature in the intrahepatic milieu and its tumor microenvironment significantly affects tumor progression. The obstacles that reduce the efficacy of CAR-T therapy in solid tumors include a lack of specific tumor antigens, limited trafficking and penetration of CAR-T cells to tumor sites, and an immunosuppressive tumor microenvironment. To overcome these obstacles, several strategies have emerged. In addition, several strategies have been developed to manage the side effects of CAR-T, including enhancing the selectivity of CARs and controlling CAR-T activity. To date, no clinical trials of CAR-T therapy against HCC have been completed. However, preclinical studies in vitro and in vivo have shown potent antitumor efficacy. Glypican-3, mucin-1, epithelial cell adhesion molecule, carcinoembryonic antigen, and other targets are currently being studied.Conclusions: The application of CAR-T therapy for liver cancer is just beginning to be explored and more research is needed. However, we ar
基金This study was supported by National Natural Science Foundation of China(82173762)111 Project(B18035,China)the Key Research and Development Program of Science and Technology Department of Sichuan Province(2022JDJQ0050,2022YFS0334).
文摘Cancer immunotherapy has significantly flourished and revolutionized the limited conventional tumor therapies,on account of its good safety and long-term memory ability.Discouragingly,low patient response rates and potential immune-related side effects make it rather challenging to literally bring immunotherapy from bench to bedside.However,it has become evident that,although the immunosuppressive tumor microenvironment(TME)plays a pivotal role in facilitating tumor progression and metastasis,it also provides various potential targets for remodeling the immunosuppressive TME,which can consequently bolster the effectiveness of antitumor response and tumor suppression.Additionally,the particular characteristics of TME,in turn,can be exploited as avenues for designing diverse precise targeting nanomedicines.In general,it is of urgent necessity to deliver nanomedicines for remodeling the immunosuppressive TME,thus improving the therapeutic outcomes and clinical translation prospects of immunotherapy.Herein,we will illustrate several formation mechanisms of immunosuppressive TME.More importantly,a variety of strategies concerning remodeling immunosuppressive TME and strengthening patients'immune systems,will be reviewed.Ultimately,we will discuss the existing obstacles and future perspectives in the development of antitumor immunotherapy.Hopefully,the thriving bloom of immunotherapy will bring vibrancy to further exploration of comprehensive cancer treatment.
基金Ramalingaswami Fellowship,Grant/Award Number:D.O.NO.BT/HRD/35/02/2006the Department of Biotechnology,&Core Research grant,Grant/Award Number:CRG/2021/003805+1 种基金Science and Engineering Research Board(SERB),Govt.of India,New DelhiSidra Medicine Precision Program,Grant/Award Numbers:5081012003,5081012002。
文摘Colorectal cancer(CRC)is a predominant life-threatening cancer,with liver and peritoneal metastases as the primary causes of death.Intestinal inflammation,a known CRC risk factor,nurtures a local inflammatory environment enriched with tumor cells,endothelial cells,immune cells,cancer-associated fibroblasts,immunosuppressive cells,and secretory growth factors.The complex interactions of aberrantly expressed cytokines,chemokines,growth factors,and matrix-remodeling enzymes promote CRC pathogenesis and evoke systemic responses that affect disease outcomes.Mounting evidence suggests that these cytokines and chemokines play a role in the progression of CRC through immunosuppression and modulation of the tumor microenvironment,which is partly achieved by the recruitment of immunosuppressive cells.These cells impart features such as cancer stem cell-like properties,drug resistance,invasion,and formation of the premetastatic niche in distant organs,promoting metastasis and aggressive CRC growth.A deeper understanding of the cytokineand chemokine-mediated signaling networks that link tumor progression and metastasis will provide insights into the mechanistic details of disease aggressiveness and facilitate the development of novel therapeutics for CRC.Here,we summarized the current knowledge of cytokine-and chemokine-mediated crosstalk in the inflammatory tumor microenvironment,which drives immunosuppression,resistance to therapeutics,and metastasis during CRC progression.We also outlined the potential of this crosstalk as a novel therapeutic target for CRC.The major cytokine/chemokine pathways involved in cancer immunotherapy are also discussed in this review.
基金supported by grants from the National Natural Science Foundation of China (No. 81171986)the Ministry of Public Health (No. 201501004)
文摘Programmed cell death 1（PD-1）/programmed cell death 1 ligand（PD-L1） blockade has shown promising effects in cancer immunotherapy. Removing the so-called ＂brakes＂ on T cell immune responses by blocking the PD-1/PDL1 check point should boost anti-tumor immunity and provide durable tumor regression for cancer patients.However, 30%–60% of patients show no response to PD-1/PD-L1 blockade. Thus, it is urgent to explore the underlying resistance mechanisms to improve sensitivity to anti-PD-1/PD-L1 therapy. We propose that the mechanisms promoting resistance mainly include T cell exclusion or exhaustion at the tumor site,immunosuppressive factors in the tumor microenvironment（TME）, and a range of tumor-intrinsic factors. This review highlights the power of studying the cellular and molecular mechanisms of resistance to improve the rational design of combination therapeutic strategies that can be translated to the clinic. Here, we briefly discuss the development of PD-1/PD-L1 blockade agents and focus on the current issues and future prospects for potential combinatorial therapeutic strategies that include anti-PD-1/PD-L1 therapy, based upon the available preclinical and clinical data.
基金supported in part by a grant from National Natural Science Foundation of China(81802255)Shanghai Pujiang Program(17PJD036,China)+6 种基金a grant from Shanghai Municipal Commission of Health and Family Planning Program(20174Y0131,China)National Key Research&Development Project(2016YFC0902300,China)major disease clinical skills enhancement program of three year action plan for promoting clinical skills and clinical innovation in municipal hospitalsShanghai Shen Kang Hospital Development Center Clinical Research Plan of SHDC(16CR1001A,China)“Dream Tutor”Outstanding Young Talents Program(fkyq1901,China)key disciplines of Shanghai Pulmonary Hospital(2017ZZ02012,China)grant of Shanghai Science and Technology Commission(16JC1405900,China)。
文摘Genomic instability remains an enabling feature of cancer and promotes malignant transformation.Alterations of DNA damage response(DDR)pathways allow genomic instability,generate neoantigens,upregulate the expression of programmed death ligand 1(PD-L1)and interact with signaling such as cyclic GMPe AMP synthase-stimulator of interferon genes(cGASe STING)signaling.Here,we review the basic knowledge of DDR pathways,mechanisms of genomic instability induced by DDR alterations,impacts of DDR alterations on immune system,and the potential applications of DDR alterations as biomarkers and therapeutic targets in cancer immunotherapy.
基金the financial support from the National Natural Science Foundation of China(81773283 and 81701684)
文摘Cancer immunotherapy has veered the paradigm of cancer treatment.Despite recent advances in immunotherapy for improved antitumor efficacy,the complicated tumor microenvironment(TME)is highly immunosuppressive,yielding both astounding and unsatisfactory clinical successes.In this regard,clinical outcomes of currently available immunotherapy are confined to the varied immune systems owing in large part to the lack of understanding of the complexity and diversity of the immune context of the TME.Various advanced designs of nanomedicines could still not fully surmount the delivery barriers of the TME.The immunosuppressive TME may even dampen the efficacy of antitumor immunity.Recently,some nanotechnology-related strategies have been inaugurated to modulate the immunosuppressive cells within the tumor immune microenvironment(TIME)for robust immunotherapeutic responses.In this review,we will highlight the current understanding of the immunosuppressive TIME and identify disparate subclasses of TIME that possess an impact on immunotherapy,especially those unique classes associated with the immunosuppressive effect.The immunoregulatory cell types inside the immunosuppressive TIME will be delineated along with the existing and potential approaches for immunosuppressive cell modulation.After introducing the various strategies,we will ultimately outline both the novel therapeutic targets and the potential issues that affect the efficacy of TIME-based nanomedicines.
基金supported by the National Natural Science Foundation of China(No.81473546)National Center for International Research(No.2015B01022)+1 种基金the Regional Collaborative Innovation Center of Tibetan Medicine(No.2017XTCX012)the Fundamental Research Funds for the Central Universities(No.2018-JYBZZ-XJSJJ011)
文摘Non-small cell lung cancer(NSCLC) accounts for 80%-85% of all lung malignancies and good diagnosis and prognosis of NSCLC are critical to the increase of its survival rate. Tumor-associated macrophages(TAM) abundantly present in numerous cancer types, and the role of TAMs in tumor biology and their prognostic value in cancer become major topics of interest. After various stimulations in the tumor microenvironment, TAMs develop into a M1(tumor-inhibitory) phenotype or M2(tumor-promoting) phenotype. Recent studies show that traditional Chinese medicine(TCM) monomers have markedly inhibitory actions for NSCLC through M1/M2 modulation. Due to the TCM monomers mainly covered five categories, i.e. terpenoids, flavonoids, polysaccharides, natural polyphenols, and alkaloids. Thus, we will discuss the regulation of TCM monomers on TAM involve in these five parts in this review. In addition, the potential role of TAMs as therapeutic targets will be discussed.
基金Supported by The Foundation of Ministry of Education of China,No.IRT0454
文摘AIM:To investigate whether tumor debris created by high-intensity focused ultrasound(HIFU)could trigger antitumor immunity in a mouse hepatocellular carcinoma model. METHODS:Twenty C57BL/6J mice bearing H22 hepatocellular carcinoma were used to generate antitumor vaccines.Ten mice underwent HIFU ablation,and the remaining 10 mice received a sham-HIFU procedure with no ultrasound irradiation.Sixty normal mice were randomly divided into HIFU vaccine,tumor vaccine and control groups.These mice were immunized with HIFU-generated vaccine,tumor-generated vaccine,and saline,respectively.In addition,20 mice bearing H22 tumors were successfully treated with HIFU ablation. The protective immunity of the vaccinated mice was investigated before and after a subsequent H22 tumor challenge.Using the 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide assay,the cytotoxicity of splenic lymphocytes co-cultured with H22 cells wasdetermined in vitro before the tumor challenge,and tumor volume and survival were measured in vivo after the challenge in each group.The mechanism was also explored by loading the vaccines with bone marrowderived dendritic cells(DCs). RESULTS:Compared to the control,HIFU therapy, tumor-generated and HIFU-generated vaccines significantly increased cytolytic activity against H22 cells in the splenocytes of the vaccinated mice(P<0.001). The tumor volume was significantly smaller in the HIFU vaccine group than in the tumor vaccine group(P <0.05)and control group(P<0.01).However,there was no tumor growth after H22 rechallenge in the HIFU therapy group.Forty-eight-day survival rate was 100%in mice in the HIFU therapy group,30%in both the HIFU vaccine and tumor vaccine groups,and 20% in the control group,indicating that the HIFU-treated mice displayed significantly longer survival than the vaccinated mice in the remaining three groups(P< 0.001).After bone marrow-derived DCs were incubated with HIFU-generated and tumor-generated vaccines, the number of mature DCs expressing MHC-Ⅱ + ,CD80 + and CD86 + mo
