Neutrophils,the most abundant leukocytes in human blood,are essential fighter immune cells against microbial infection.Based on the finding that neutrophils can either restrict or promote cancer progression,tumor-asso...Neutrophils,the most abundant leukocytes in human blood,are essential fighter immune cells against microbial infection.Based on the finding that neutrophils can either restrict or promote cancer progression,tumor-associated neutrophils(TAN)are classified into anti-tumor N1 and pro-tumor N2 subsets.One of the major mechanisms underlying the tumor-promoting function of N2-TANs is suppression of adaptive immune cells,in particular,cytotoxic T lymphocytes.Currently,no established methodologies are available that can unequivocally distinguish immunosuppressive TANs and granulocytic/polymorphonuclear myeloid-derived suppressor cells(G/PMN-MDSC).In view of the critical role of PMN-MDSCs in immune evasion and resistance to cancer immunotherapy,as established from data obtained with diverse cancer models,therapeutic strategies targeting these cells have been actively developed to enhance the efficacy of immunotherapy.Here,we have reviewed the available literature on strategies targeting PMN-MDSCs and summarized the findings into four categories:(1)depletion of existing PMN-MDSCs,(2)blockade of the development of PMNMDSCs,(3)blockade of PMN-MDSC recruitment,(4)inhibition of immunosuppressive function.Owing to their high mobility to inflamed organs and ability to trespass the blood-brain barrier,neutrophils are outstanding candidate carriers in nanoparticle-based therapies.Another attractive application of neutrophils in cancer therapy is the use of neutrophil membrane-derived nanovesicles as a surrogate of extracellular vesicles for more efficient and scalable drug delivery.In the second part of the review,we have highlighted recent advances in the field of neutrophil-based cancer drug delivery.Overall,we believe that neutrophil-based therapeutics are a rapidly growing area of cancer therapy with significant potential benefits.展开更多
Neutrophils play an essential role in the defense against bacterial infections and orchestrate both the innate and adaptive immune responses.With their abundant numbers,diverse function and short life span,these cells...Neutrophils play an essential role in the defense against bacterial infections and orchestrate both the innate and adaptive immune responses.With their abundant numbers,diverse function and short life span,these cells are at the forefront of immune responses,and have gained attention in recent years because of their presence in tumor sites.Neutrophil involvement pertains to tumor cells'ability to construct a suitable tumor microenvironment(TME)that accelerates their own growth and malignancy,by facilitating their interaction with surrounding cells through the circulatory and lymphatic systems,thereby influencing tumor development and progression.Studies have indicated both pro-and anti-tumor properties of infiltrating neutrophils.The TME can exploit neutrophil function,recruitment,and even production,thus resulting in pro-tumor properties of neutrophils,including promotion of genetic instability,tumor cell proliferation,angiogenesis and suppression of anti-tumor or inflammatory response.In contrast,neutrophils can mediate anti-tumor resistance by direct cytotoxicity to the tumor cells or by facilitating anti-tumor functions via crosstalk with T cells.Here,we summarize current knowledge regarding the effects of neutrophil heterogeneity under homeostatic and tumor conditions,including neutrophil phenotype and function,in cancer biology.展开更多
Tumor microenvironment contributes to poor prognosis of pancreatic adenocarcinoma(PAAD)patients.Proper regulation could improve survival.Melatonin is an endogenous hormone that delivers multiple bioactivities.Here we ...Tumor microenvironment contributes to poor prognosis of pancreatic adenocarcinoma(PAAD)patients.Proper regulation could improve survival.Melatonin is an endogenous hormone that delivers multiple bioactivities.Here we showed that pancreatic melatonin level is associated with patients'survival.In PAAD mice models,melatonin supplementation suppressed tumor growth,while blockade of melatonin pathway exacerbated tumor progression.This anti-tumor effect was independent of cytotoxicity but associated with tumor-associated neutrophils(TANs),and TANs depletion reversed effects of melatonin.Melatonin induced TANs infiltration and activation,therefore induced cell apoptosis of PAAD cells.Cytokine arrays revealed that melatonin had minimal impact on neutrophils but induced secretion of Cxcl2 from tumor cells.Knockdown of Cxcl2 in tumor cells abolished neutrophil migration and activation.Melatonin-induced neutrophils presented an N1-like anti-tumor phenotype,with increased neutrophil extracellular traps(NETs)causing tumor cell apoptosis through cell-to-cell contact.Proteomics analysis revealed that this reactive oxygen species(ROS)-mediated inhibition was fueled by fatty acid oxidation(FAO)in neutrophils,while FAO inhibitor abolished the anti-tumor effect.Analysis of PAAD patient specimens revealed that CXCL2 expression was associated with neutrophil infiltration.CXCL2,or TANs,combined with NET marker,can better predict patients'prognosis.Collectively,we discovered an anti-tumor mechanism of melatonin through recruiting N1-neutrophils and beneficial NET formation.展开更多
In recent years, the numerous roles of neutrophils have gained increasing attention. Beyond their traditional role in infection control, research on neutrophils has expanded to their roles in tumor regulation. It has ...In recent years, the numerous roles of neutrophils have gained increasing attention. Beyond their traditional role in infection control, research on neutrophils has expanded to their roles in tumor regulation. It has been found that neutrophils present in the tumor microenvironment, tumor-associated neutrophils (TANs), exert complex and apparently opposing effects by reducing and promoting tumor growth and progression in response to various factors in the tumor microenvironment. In addition, recent studies have reported the heterogeneity and complex tumor regulation of circulating neutrophils. The present paper provides a summary of the related research progress.展开更多
The dynamic interplay between tumor cells and immune cells in the microenvironment plays a crucial role in determining disease severity and therapeutic outcome in cancer.Myeloid cells are the most abundantly available...The dynamic interplay between tumor cells and immune cells in the microenvironment plays a crucial role in determining disease severity and therapeutic outcome in cancer.Myeloid cells are the most abundantly available cell population in the tumor microenvironment.Myeloid cells have been shown to exist in diverse phenotypes and play both antitumoral and protumoral roles in cancer.Understanding the biology of myeloid cells can lay the foundation for the development of therapeutic strategies aimed at enhancing the antitumoral role of myeloid cells.This article presents an overview of the role of myeloid cells in tumor development and various mechanisms by which myeloid cells aid tumor progression.Existing drugs against cancer that utilize myeloid cells and the role of myeloid cells in drug resistance are also discussed.展开更多
基金partly supported by a graduate fellowship from China Scholarship Council(Grant No.201708340071)partly supported by a Career Catalyst Research Grant(Grant No.18548293)from the Susan G.Komen Foundation+1 种基金a Cancer Research Grant from the Mary Kay Foundationa Research Grant from the Elsa U.Pardee Foundation。
文摘Neutrophils,the most abundant leukocytes in human blood,are essential fighter immune cells against microbial infection.Based on the finding that neutrophils can either restrict or promote cancer progression,tumor-associated neutrophils(TAN)are classified into anti-tumor N1 and pro-tumor N2 subsets.One of the major mechanisms underlying the tumor-promoting function of N2-TANs is suppression of adaptive immune cells,in particular,cytotoxic T lymphocytes.Currently,no established methodologies are available that can unequivocally distinguish immunosuppressive TANs and granulocytic/polymorphonuclear myeloid-derived suppressor cells(G/PMN-MDSC).In view of the critical role of PMN-MDSCs in immune evasion and resistance to cancer immunotherapy,as established from data obtained with diverse cancer models,therapeutic strategies targeting these cells have been actively developed to enhance the efficacy of immunotherapy.Here,we have reviewed the available literature on strategies targeting PMN-MDSCs and summarized the findings into four categories:(1)depletion of existing PMN-MDSCs,(2)blockade of the development of PMNMDSCs,(3)blockade of PMN-MDSC recruitment,(4)inhibition of immunosuppressive function.Owing to their high mobility to inflamed organs and ability to trespass the blood-brain barrier,neutrophils are outstanding candidate carriers in nanoparticle-based therapies.Another attractive application of neutrophils in cancer therapy is the use of neutrophil membrane-derived nanovesicles as a surrogate of extracellular vesicles for more efficient and scalable drug delivery.In the second part of the review,we have highlighted recent advances in the field of neutrophil-based cancer drug delivery.Overall,we believe that neutrophil-based therapeutics are a rapidly growing area of cancer therapy with significant potential benefits.
基金A.Y.H. was supported by NRSA Institutional Postdoctoral Training grant T32 (Grant No. 5T32HL066987-20)C.S. was supported by grants from the National Natural Science Foundation of China (Grant No. 82001661)+1 种基金F.X.M. and C.S. were supported by the Haihe Laboratory of Cell Ecosystem Innovation Fund (Grant No. HH22KYZX0019)F.X.M. was supported by the National Natural Science Foundation of China (Grant No. 82171756)
文摘Neutrophils play an essential role in the defense against bacterial infections and orchestrate both the innate and adaptive immune responses.With their abundant numbers,diverse function and short life span,these cells are at the forefront of immune responses,and have gained attention in recent years because of their presence in tumor sites.Neutrophil involvement pertains to tumor cells'ability to construct a suitable tumor microenvironment(TME)that accelerates their own growth and malignancy,by facilitating their interaction with surrounding cells through the circulatory and lymphatic systems,thereby influencing tumor development and progression.Studies have indicated both pro-and anti-tumor properties of infiltrating neutrophils.The TME can exploit neutrophil function,recruitment,and even production,thus resulting in pro-tumor properties of neutrophils,including promotion of genetic instability,tumor cell proliferation,angiogenesis and suppression of anti-tumor or inflammatory response.In contrast,neutrophils can mediate anti-tumor resistance by direct cytotoxicity to the tumor cells or by facilitating anti-tumor functions via crosstalk with T cells.Here,we summarize current knowledge regarding the effects of neutrophil heterogeneity under homeostatic and tumor conditions,including neutrophil phenotype and function,in cancer biology.
基金partially supported by the Research Council of the University of Hong Kong(project codes:104004092 and 104004460,China)the Wong's donation(project code:200006276,HKSAR)+4 种基金a donation from the Gaia Family Trust of New Zealand(project code:200007008)the Research Grants Committee(RGC)of Hong Kong,HKSAR(Project Codes:740608,766211,17152116 and 17121419,China)the Health and Medical Research Fund(Project code:15162961 and 16172751,HKSAR)the Enhanced New Staff Start-up Fund(Project code:204610519,HKSAR)the Pre-emptive Retention Fund(Project code:202007002,HKSAR)。
文摘Tumor microenvironment contributes to poor prognosis of pancreatic adenocarcinoma(PAAD)patients.Proper regulation could improve survival.Melatonin is an endogenous hormone that delivers multiple bioactivities.Here we showed that pancreatic melatonin level is associated with patients'survival.In PAAD mice models,melatonin supplementation suppressed tumor growth,while blockade of melatonin pathway exacerbated tumor progression.This anti-tumor effect was independent of cytotoxicity but associated with tumor-associated neutrophils(TANs),and TANs depletion reversed effects of melatonin.Melatonin induced TANs infiltration and activation,therefore induced cell apoptosis of PAAD cells.Cytokine arrays revealed that melatonin had minimal impact on neutrophils but induced secretion of Cxcl2 from tumor cells.Knockdown of Cxcl2 in tumor cells abolished neutrophil migration and activation.Melatonin-induced neutrophils presented an N1-like anti-tumor phenotype,with increased neutrophil extracellular traps(NETs)causing tumor cell apoptosis through cell-to-cell contact.Proteomics analysis revealed that this reactive oxygen species(ROS)-mediated inhibition was fueled by fatty acid oxidation(FAO)in neutrophils,while FAO inhibitor abolished the anti-tumor effect.Analysis of PAAD patient specimens revealed that CXCL2 expression was associated with neutrophil infiltration.CXCL2,or TANs,combined with NET marker,can better predict patients'prognosis.Collectively,we discovered an anti-tumor mechanism of melatonin through recruiting N1-neutrophils and beneficial NET formation.
文摘In recent years, the numerous roles of neutrophils have gained increasing attention. Beyond their traditional role in infection control, research on neutrophils has expanded to their roles in tumor regulation. It has been found that neutrophils present in the tumor microenvironment, tumor-associated neutrophils (TANs), exert complex and apparently opposing effects by reducing and promoting tumor growth and progression in response to various factors in the tumor microenvironment. In addition, recent studies have reported the heterogeneity and complex tumor regulation of circulating neutrophils. The present paper provides a summary of the related research progress.
文摘The dynamic interplay between tumor cells and immune cells in the microenvironment plays a crucial role in determining disease severity and therapeutic outcome in cancer.Myeloid cells are the most abundantly available cell population in the tumor microenvironment.Myeloid cells have been shown to exist in diverse phenotypes and play both antitumoral and protumoral roles in cancer.Understanding the biology of myeloid cells can lay the foundation for the development of therapeutic strategies aimed at enhancing the antitumoral role of myeloid cells.This article presents an overview of the role of myeloid cells in tumor development and various mechanisms by which myeloid cells aid tumor progression.Existing drugs against cancer that utilize myeloid cells and the role of myeloid cells in drug resistance are also discussed.
