Lung cancer-derived exosomes are a kind of valuable and clinically-predictable biomarkers for lung cancer, but they have the limitations in individual differences when being applied in liquid biopsy. To improve their ...Lung cancer-derived exosomes are a kind of valuable and clinically-predictable biomarkers for lung cancer, but they have the limitations in individual differences when being applied in liquid biopsy. To improve their application value and accuracy in clinical diagnosis, a dual-labelled electrochemical method is herein reported for precise assessment of lung cancer-derived exosomes. To do so, two probes are prepared for the dual labeling of exosome membrane to run DNA assembly reactions: One is modified with cholesterol and can insert into exosome membrane through hydrophobic interaction;another one is linked with programmed death ligand-1(PD-L1) antibody and can bind to exosome surface-expressing PD-L1 via specific immunoreaction. Quantum dots-tagged signal strands are used to collect respective DNA products, and produce stripping signals corresponding to the amounts of total exosome and surfaceexpressing PD-L1, respectively. A wide linear relationship is established for the quantitative determination of lung cancer-derived exosomes in the range from 103to 1010particles/m L, whereas the ratiometric value of the two stripping signals is proven to have a better diagnostic use in screening and staging of lung cancer when being applied to clinical samples. Therefore, our method might provide a new insight into precise diagnosis of lung cancer, and offer sufficient information to refiect the biomarker level and guide the personalized treatment level even at an early stage in clinic.展开更多
To date,IgG in the tumor microenvironment(TME)has been considered a product of B cells and serves as an antitumor antibody.However,in this study,using a monoclonal antibody against cancer-derived IgG(Cancer-IgG),we fo...To date,IgG in the tumor microenvironment(TME)has been considered a product of B cells and serves as an antitumor antibody.However,in this study,using a monoclonal antibody against cancer-derived IgG(Cancer-IgG),we found that cancer cells could secrete IgG into the TME.Furthermore,Cancer-IgG,which carries an abnormal sialic acid modification in the CH1 domain,directly inhibited effector T-cell proliferation and significantly promoted tumor growth by reducing CD4^(+)and CD8^(+)T-cell infiltration into tumor tissues.Mechanistic studies showed that the immunosuppressive effect of sialylated Cancer-IgG is dependent on its sialylation and binding to sialic acid-binding immunoglobulin-type lectins(Siglecs)on effector CD4^(+)and CD8^(+)T cells.Importantly,we show that several Siglecs are overexpressed on effector T cells from cancer patients,but not those from healthy donors.These findings suggest that sialylated Cancer-IgG may be a ligand for Siglecs,which may serve as potential checkpoint proteins and mediate tumor immune evasion.展开更多
基金supported by the National Natural Science Foundation of China (Nos. 81972799, 82202834, and 81871449)。
文摘Lung cancer-derived exosomes are a kind of valuable and clinically-predictable biomarkers for lung cancer, but they have the limitations in individual differences when being applied in liquid biopsy. To improve their application value and accuracy in clinical diagnosis, a dual-labelled electrochemical method is herein reported for precise assessment of lung cancer-derived exosomes. To do so, two probes are prepared for the dual labeling of exosome membrane to run DNA assembly reactions: One is modified with cholesterol and can insert into exosome membrane through hydrophobic interaction;another one is linked with programmed death ligand-1(PD-L1) antibody and can bind to exosome surface-expressing PD-L1 via specific immunoreaction. Quantum dots-tagged signal strands are used to collect respective DNA products, and produce stripping signals corresponding to the amounts of total exosome and surfaceexpressing PD-L1, respectively. A wide linear relationship is established for the quantitative determination of lung cancer-derived exosomes in the range from 103to 1010particles/m L, whereas the ratiometric value of the two stripping signals is proven to have a better diagnostic use in screening and staging of lung cancer when being applied to clinical samples. Therefore, our method might provide a new insight into precise diagnosis of lung cancer, and offer sufficient information to refiect the biomarker level and guide the personalized treatment level even at an early stage in clinic.
基金supported by research grants to X.Qiu from the key support projects of the National Natural Science Foundation’s major research program(91642206)major international cooperation projects of the National Natural Science Foundation(81320108020)+2 种基金research institute fund of the NHC Key Laboratory of Medical Immunology,Peking University(BMU2018JDJS010)the Science Technology and Innovation Committee of Shenzhen Municipality(JCYJ20170413141047772)nonprofit central research institute fund of the Chinese Academy of Medical Sciences(2018PT31039).
文摘To date,IgG in the tumor microenvironment(TME)has been considered a product of B cells and serves as an antitumor antibody.However,in this study,using a monoclonal antibody against cancer-derived IgG(Cancer-IgG),we found that cancer cells could secrete IgG into the TME.Furthermore,Cancer-IgG,which carries an abnormal sialic acid modification in the CH1 domain,directly inhibited effector T-cell proliferation and significantly promoted tumor growth by reducing CD4^(+)and CD8^(+)T-cell infiltration into tumor tissues.Mechanistic studies showed that the immunosuppressive effect of sialylated Cancer-IgG is dependent on its sialylation and binding to sialic acid-binding immunoglobulin-type lectins(Siglecs)on effector CD4^(+)and CD8^(+)T cells.Importantly,we show that several Siglecs are overexpressed on effector T cells from cancer patients,but not those from healthy donors.These findings suggest that sialylated Cancer-IgG may be a ligand for Siglecs,which may serve as potential checkpoint proteins and mediate tumor immune evasion.
