Dear Editor,The coronavirus infectious disease 2019(COVID-19)outbreak is seriously endangering human health.Most patients with severe COVID-19 are characterized by sustained cytokine production and hyper-inflammation,...Dear Editor,The coronavirus infectious disease 2019(COVID-19)outbreak is seriously endangering human health.Most patients with severe COVID-19 are characterized by sustained cytokine production and hyper-inflammation,which is known as cytokine storm syndrome.1-3 Elaborating the anti-inflammatory response is crucial to these patients,and interieukin-6(IL6)inhibitors and steroids have been recommended in clinical practice.1 However,after the cytokine storm phase,the host immune response to sepsis may develop into a protracted immunosuppressive phase.展开更多
Glioblastoma(GBM,WHO grade IV glioma)is the most common and lethal malignant brain tumor in aduts with a dismal prognosis.The extracellular matrix(ECM)supports GBM progression by promoting tumor cell proliferation,mig...Glioblastoma(GBM,WHO grade IV glioma)is the most common and lethal malignant brain tumor in aduts with a dismal prognosis.The extracellular matrix(ECM)supports GBM progression by promoting tumor cell proliferation,migration,and immune escape.Uridine diphosphate(UDP)-glucose 6-dehydrogenase(UGDH)is the rate-limiting enzyme that catalyzes the biosynthesis of glycosaminoglycans that are the principal component of the CNS ECM.We investigated how targeting UGDH in GBM infuence$the GBM immune microenvironment,including tumor-associated microglia/macrophages(TAMs)and T cells.TAMs are the main im-mune effector cells in GBM and can directly target tumor cells if properly activated.In co-cultures of GBM cells and human primary macrophages,UGDH knockdown in GBM cells pro-moted macrophage phagocytosis and M-like polarization.In orthotropic human GBM xeno-grafts and syngeneic mouse glioma models,targeting UGDH decreased ECM deposition,increased TAM phagocytosis marker expression,reduced M2-like TAMS and inhibited tumor growth.UGDH knockdown in GBM cells also promoted cytotoxic T cell ifltration and activa-tion in orthotopic syngeneic mouse glioma models.The potent and in-human-use small mole-cule GAG synthesis inhibitor 4-methylumbelliferone(4-MU)was found to inhibit GBM cell proliferation and migration in vitro,mimic the macrophage and T-cell responses to UGDH knockdown in vitro and in vivo and inhibit growth of orthotopic murine GBM.Our study shows that UGDH supports GBM growth through multiple mechanisms and supports the development of ECM-based therapeutic strategies to simultaneously target tumor cells and their microenvi-ronment.展开更多
基金We thank the Beijing Talents Foundation(2017000021223ZK30)Beijing Lab Foundation+1 种基金Special Funds for COVID-19 Prevention and Control of West China Hospital of Sichuan University(HX-2019-nCoV-049)the National Key Research and Developm ent Program of China(SQ2020YFF0426498).
文摘Dear Editor,The coronavirus infectious disease 2019(COVID-19)outbreak is seriously endangering human health.Most patients with severe COVID-19 are characterized by sustained cytokine production and hyper-inflammation,which is known as cytokine storm syndrome.1-3 Elaborating the anti-inflammatory response is crucial to these patients,and interieukin-6(IL6)inhibitors and steroids have been recommended in clinical practice.1 However,after the cytokine storm phase,the host immune response to sepsis may develop into a protracted immunosuppressive phase.
基金This work was supported by grants from NIH R01NS091165(S.X.),R01 NS099460(M Ying),R01 NS096754(J Laterra),and R01 NS076759(J Laterra)。
文摘Glioblastoma(GBM,WHO grade IV glioma)is the most common and lethal malignant brain tumor in aduts with a dismal prognosis.The extracellular matrix(ECM)supports GBM progression by promoting tumor cell proliferation,migration,and immune escape.Uridine diphosphate(UDP)-glucose 6-dehydrogenase(UGDH)is the rate-limiting enzyme that catalyzes the biosynthesis of glycosaminoglycans that are the principal component of the CNS ECM.We investigated how targeting UGDH in GBM infuence$the GBM immune microenvironment,including tumor-associated microglia/macrophages(TAMs)and T cells.TAMs are the main im-mune effector cells in GBM and can directly target tumor cells if properly activated.In co-cultures of GBM cells and human primary macrophages,UGDH knockdown in GBM cells pro-moted macrophage phagocytosis and M-like polarization.In orthotropic human GBM xeno-grafts and syngeneic mouse glioma models,targeting UGDH decreased ECM deposition,increased TAM phagocytosis marker expression,reduced M2-like TAMS and inhibited tumor growth.UGDH knockdown in GBM cells also promoted cytotoxic T cell ifltration and activa-tion in orthotopic syngeneic mouse glioma models.The potent and in-human-use small mole-cule GAG synthesis inhibitor 4-methylumbelliferone(4-MU)was found to inhibit GBM cell proliferation and migration in vitro,mimic the macrophage and T-cell responses to UGDH knockdown in vitro and in vivo and inhibit growth of orthotopic murine GBM.Our study shows that UGDH supports GBM growth through multiple mechanisms and supports the development of ECM-based therapeutic strategies to simultaneously target tumor cells and their microenvi-ronment.
