Like the wars predating the First World War where human foot soldiers were deemed tools in the battlefield against an enemy, so too are the host immune cells of a patient battling a malignant gastric cancer. Indeed, t...Like the wars predating the First World War where human foot soldiers were deemed tools in the battlefield against an enemy, so too are the host immune cells of a patient battling a malignant gastric cancer. Indeed, the tumour microenvironment resembles a battlefield, where the patient's immune cells are the defence against invading tumour cells. However, the relationship between different immune components of the host response to cancer is more complex than an "us against them" model. Components of the immune system inadvertently work against the interests of the host and become pro-tumourigenic while other components soldier on against the common enemy – the tumour cell.展开更多
TO THE EDITOR:Characterization of the tumor-infiltrating B cell immunoglobulin(Ig)repertoire is critical to understanding B cell immunity in tumors and developing monoclonal antibody therapy.However,the generation of ...TO THE EDITOR:Characterization of the tumor-infiltrating B cell immunoglobulin(Ig)repertoire is critical to understanding B cell immunity in tumors and developing monoclonal antibody therapy.However,the generation of specific antibodies for cancer therapy1,2 is a major endeavor,involving a lengthy process of antigen identification,immunization,hybridoma production and,in most cases,antibody humanization.As a radical departure from the conventional approach,we hereby describe a rapid and potentially en masse identification of cancer-specific antibodies directly from human cancer tissues by de novo assembly from transcriptome and genome sequences.Our integrated computational framework was developed and successfully tested for antibody discovery by mining 1945 solid tumor RNA-sequencing-based samples for abundant Ig CDR3 sequences among the TCGA database of glioblastoma multiforme(GBM),lower grade glioma(LGG),lung adenocarcinoma(LUAD),lung squamous carcinoma(LUSC),pancreatic adenocarcinoma(PAAD),and skin cutaneous melanoma(SKCM).展开更多
Dear editor,Lung carcinoma is responsible for the highest fatal-ity rate among cancer-related deaths globally,with lung adenocarcinoma(LADC)emerging as the prevailing sub-type.
A recent meta-analysis revealed the contribution of the SIGLEC6 locus to the risk of developing systemic lupus erythematosus(SLE).However,no specific Siglec(sialic acid-binding immunoglobulin-like lectin)genes(Siglecs...A recent meta-analysis revealed the contribution of the SIGLEC6 locus to the risk of developing systemic lupus erythematosus(SLE).However,no specific Siglec(sialic acid-binding immunoglobulin-like lectin)genes(Siglecs)have been implicated in the pathogenesis of SLE.Here,we performed in silico analysis of the function of three major protective alleles in the locus and found that these alleles were expression quantitative trait loci that enhanced expression of the adjacent SIGLEC12 gene.These data suggest that SIGLEC12 may protect against the development of SLE in Asian populations.Consistent with human genetic data,we identified two missense mutations in lupus-prone B6.NZMSle1/Sle2/Sle3(Sle1–3)mice in Siglece,which is the murine Siglec with the greatest homology to human SIGLEC12.Since the mutations resulted in reduced binding of Siglec E to splenic cells,we evaluated whether Siglece−/−mice had SLE phenotypes.We found that Siglece−/−mice showed increased autoantibody production,glomerular immune complex deposition and severe renal pathology reminiscent of human SLE nephropathy.Our data demonstrate that the Siglec genes confer resistance to SLE in mice and humans.展开更多
Oligodendrocytes play a critical role in neuroprotection by both remyelination-dependent and remyelination-independent mechanisms and confer protection in both inflammatory and degenerative diseases that involve the c...Oligodendrocytes play a critical role in neuroprotection by both remyelination-dependent and remyelination-independent mechanisms and confer protection in both inflammatory and degenerative diseases that involve the central nervous system,including multiple sclerosis,Alzheimer’s disease and potentially Parkinson’s disease.1,2,3,4 Although accumulating data have supported a major role for inflammation in the susceptibility of oligodendrocytes to cuprizone,the molecular pathways that regulate oligodendrocyte survival have not been well established.Here,we report that the targeted mutation of either Cd24 or Siglecg,which forms an axis that selectively regulates the innate inflammatory response to danger-associated molecular patterns(DAMPs),protects mice against cuprizone-induced oligodendrocyte loss.Moreover,the systemic administration of CD24Fc,which is known to stimulate Siglec G signaling and suppress the inflammatory response in vivo,protects oligodendrocytes against chronic exposure to cuprizone.Our data suggest that the host response to cellular injury actively participates in oligodendrocyte loss and provides a new approach to maintain oligodendrocytes under pathological conditions.展开更多
Natural killer(NK)cells are attractive effector cells of the innate immune system against human immunodeficiency virus(HIV)and cancer.However,NK cell therapies are limited by the fact that target cells evade NK cells,...Natural killer(NK)cells are attractive effector cells of the innate immune system against human immunodeficiency virus(HIV)and cancer.However,NK cell therapies are limited by the fact that target cells evade NK cells,for example,in latent reservoirs(in HIV)or through upregulation of inhibitory signals(in cancer).To address this limitation,we describe a biodegradable nanoparticlebased“priming”approach to enhance the cytotoxic efficacy of peripheral blood mononuclear cell-derived NK cells.We present poly(lactic-co-glycolic acid)(PLGA)nanodepots(NDs)that co-encapsulate prostratin,a latency-reversing agent,and anti-CD25(aCD25),a cell surface binding antibody,to enhance primary NK cell function against HIV and cancer.We utilize a nanoemulsion synthesis scheme to encapsulate both prostratin and aCD25 within the PLGA NDs(termed Pro-aCD25-NDs).Physicochemical characterization studies of the NDs demonstrated that our synthesis scheme resulted in stable and monodisperse Pro-aCD25-NDs.The NDs successfully released both active prostratin and anti-CD25,and with controllable release kinetics.When Pro-aCD25-NDs were administered in an in vitro model of latent HIV and acute T cell leukemia using J-Lat 10.6 cells,the NDs were observed to prime J-Lat cells resulting in significantly increased NK cell-mediated cytotoxicity compared to free prostratin plus anti-CD25,and other controls.These findings demonstrate the feasibility of using our Pro-aCD25-NDs to prime target cells for enhancing the cytotoxicity of NK cells as antiviral or antitumor agents.展开更多
The X-linked Trap1a gene encodes the tumor rejection antigen P1A,which is expressed in fetal tissues and multiple lineages of tumor cells.The function of this gene remains unknown.Using chimeric mice with wild-type(WT...The X-linked Trap1a gene encodes the tumor rejection antigen P1A,which is expressed in fetal tissues and multiple lineages of tumor cells.The function of this gene remains unknown.Using chimeric mice with wild-type(WT)and Trap1a^(−/y)bone marrow,we show that Trap1a^(−/y)donor cells are capable of generating most lineages of hematopoietic cells,with the notable exception of T cells.Deletion of Trap1a selectively arrests T-cell development at double-negative stage 1(DN1,with a CD4^(−)CD8^(−)CD25^(−)CD44^(+)phenotype).Because Trap1a is expressed in Lin^(−)Sca-1^(+)c-Kit^(+)and common lymphoid progenitors but not in immature thymocytes(DN1-DN4),Trap1a mutations affect the differentiation potential of progenitor cells without directly acting on T cells.Despite a similarity in the blockade of DN1 to DN2 transition,the Trap1a^(−/y)DN1 cells have normal expression of c-Kit,in contrast to what was reported in the Notch1^(−/−)DN1.Complementary DNA profiling of Trap1a^(−/y)and WT embryonic stem cells shows that Trap1a does not regulate the Notch pathway.Our data reveal that Trap1a is an X-linked regulator that affects the differentiation potential of progenitor cells into T cells through a Notch-independent mechanism and identify an important function for the Trap1a gene.展开更多
Multiple myeloma （MM） remains an incurable neoplastic disease, although high-dose chemotherapy supported by autologous stem cells, and the latest integration of several novel agents, including thalidomide, bortezomi...Multiple myeloma （MM） remains an incurable neoplastic disease, although high-dose chemotherapy supported by autologous stem cells, and the latest integration of several novel agents, including thalidomide, bortezomib and lenalidomide, into each step of therapeutics have substantially improved the outcome of patients with MM.1-5 Herein, we gave our own considerations on some promising directions in the near future, aiming at further improving the survival and the quality of life of MM patients, and even achieving our final goal of the cure of MM, including highlighting stratified and individualized therapies, pursuing novel targets and strategies, unraveling the biological characteristics of myeloma initiation cells and strengthening post-transplant immunotherapies.展开更多
文摘Like the wars predating the First World War where human foot soldiers were deemed tools in the battlefield against an enemy, so too are the host immune cells of a patient battling a malignant gastric cancer. Indeed, the tumour microenvironment resembles a battlefield, where the patient's immune cells are the defence against invading tumour cells. However, the relationship between different immune components of the host response to cancer is more complex than an "us against them" model. Components of the immune system inadvertently work against the interests of the host and become pro-tumourigenic while other components soldier on against the common enemy – the tumour cell.
文摘TO THE EDITOR:Characterization of the tumor-infiltrating B cell immunoglobulin(Ig)repertoire is critical to understanding B cell immunity in tumors and developing monoclonal antibody therapy.However,the generation of specific antibodies for cancer therapy1,2 is a major endeavor,involving a lengthy process of antigen identification,immunization,hybridoma production and,in most cases,antibody humanization.As a radical departure from the conventional approach,we hereby describe a rapid and potentially en masse identification of cancer-specific antibodies directly from human cancer tissues by de novo assembly from transcriptome and genome sequences.Our integrated computational framework was developed and successfully tested for antibody discovery by mining 1945 solid tumor RNA-sequencing-based samples for abundant Ig CDR3 sequences among the TCGA database of glioblastoma multiforme(GBM),lower grade glioma(LGG),lung adenocarcinoma(LUAD),lung squamous carcinoma(LUSC),pancreatic adenocarcinoma(PAAD),and skin cutaneous melanoma(SKCM).
基金This research was supported in part by the Japan Agency for Medical Research and Development(AMED)(JP15ck0106096 to TK)Japan Science and Tech-nology Agency(JST)Core Research for Evolutionary Science and Technology(JPMJCR1689 to RH)+5 种基金Artifi-cial Intelligence,Big Data,IoT,Cyber Security Integration Project of the Public/Private R&D Investment Strategic Expansion Program(JPMJCR18Y4 to RH)the Japan Soci-ety for the Promotion of Science(JSPS)Grant-in-Aid for Scientific Research(S)(17H06162 to HN),Grant-in-Aid for Scientific Research(B)(20H03695 to KS),Grants-in-Aid for the Tailor-Made Medical Treatment Program(BioBank Japan Project)from the Japanese Ministry of Education,Culture,Sports,ScienceandTechnology(MEXT),Princess Takamatsu Cancer Research Fund,and National Cancer Center Research and Development Fund(NCC Biobank and NCC Core Facility).The J-MICC study was supported by Grants-in-Aid for Scientific Research for Priority Areas of Cancer(No.17015018 to KW)Innovative Areas(No.221S0001 to KW)from MEXTby JSPS Grant-in-Aid for Scientific Research Grant(No.16H06277[CoBiA])The JPHC Study was supported by National Cancer Center Research and Development Fund since 2011(latest grant number:2020-J4)and a Grant-in-Aid for Cancer Research from the Ministry of Health,Labor and Welfare of Japan(1989-2010).ToMMoissupportedinpartbyMEXT-JSTand AMED(most recent grant numbers:JP20km0105001 and JP20km0105002)Iwate Tohoku Medical Megabank Orga-nization(Iwate Medical University)is supported in part by MEXT-JST and AMED(most recent grant numbers:JP20km0105003 and JP20km0105004).
文摘Dear editor,Lung carcinoma is responsible for the highest fatal-ity rate among cancer-related deaths globally,with lung adenocarcinoma(LADC)emerging as the prevailing sub-type.
基金by Grants(AI064350,AG036690)from the National Institutes of Health.
文摘A recent meta-analysis revealed the contribution of the SIGLEC6 locus to the risk of developing systemic lupus erythematosus(SLE).However,no specific Siglec(sialic acid-binding immunoglobulin-like lectin)genes(Siglecs)have been implicated in the pathogenesis of SLE.Here,we performed in silico analysis of the function of three major protective alleles in the locus and found that these alleles were expression quantitative trait loci that enhanced expression of the adjacent SIGLEC12 gene.These data suggest that SIGLEC12 may protect against the development of SLE in Asian populations.Consistent with human genetic data,we identified two missense mutations in lupus-prone B6.NZMSle1/Sle2/Sle3(Sle1–3)mice in Siglece,which is the murine Siglec with the greatest homology to human SIGLEC12.Since the mutations resulted in reduced binding of Siglec E to splenic cells,we evaluated whether Siglece−/−mice had SLE phenotypes.We found that Siglece−/−mice showed increased autoantibody production,glomerular immune complex deposition and severe renal pathology reminiscent of human SLE nephropathy.Our data demonstrate that the Siglec genes confer resistance to SLE in mice and humans.
文摘Oligodendrocytes play a critical role in neuroprotection by both remyelination-dependent and remyelination-independent mechanisms and confer protection in both inflammatory and degenerative diseases that involve the central nervous system,including multiple sclerosis,Alzheimer’s disease and potentially Parkinson’s disease.1,2,3,4 Although accumulating data have supported a major role for inflammation in the susceptibility of oligodendrocytes to cuprizone,the molecular pathways that regulate oligodendrocyte survival have not been well established.Here,we report that the targeted mutation of either Cd24 or Siglecg,which forms an axis that selectively regulates the innate inflammatory response to danger-associated molecular patterns(DAMPs),protects mice against cuprizone-induced oligodendrocyte loss.Moreover,the systemic administration of CD24Fc,which is known to stimulate Siglec G signaling and suppress the inflammatory response in vivo,protects oligodendrocytes against chronic exposure to cuprizone.Our data suggest that the host response to cellular injury actively participates in oligodendrocyte loss and provides a new approach to maintain oligodendrocytes under pathological conditions.
基金Research reported in this publication was supported in part by the George Washington Cancer Center and by the National Institute Of Allergy And Infectious Diseases of the National Institutes of Health under Award Number R21AI136102The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
文摘Natural killer(NK)cells are attractive effector cells of the innate immune system against human immunodeficiency virus(HIV)and cancer.However,NK cell therapies are limited by the fact that target cells evade NK cells,for example,in latent reservoirs(in HIV)or through upregulation of inhibitory signals(in cancer).To address this limitation,we describe a biodegradable nanoparticlebased“priming”approach to enhance the cytotoxic efficacy of peripheral blood mononuclear cell-derived NK cells.We present poly(lactic-co-glycolic acid)(PLGA)nanodepots(NDs)that co-encapsulate prostratin,a latency-reversing agent,and anti-CD25(aCD25),a cell surface binding antibody,to enhance primary NK cell function against HIV and cancer.We utilize a nanoemulsion synthesis scheme to encapsulate both prostratin and aCD25 within the PLGA NDs(termed Pro-aCD25-NDs).Physicochemical characterization studies of the NDs demonstrated that our synthesis scheme resulted in stable and monodisperse Pro-aCD25-NDs.The NDs successfully released both active prostratin and anti-CD25,and with controllable release kinetics.When Pro-aCD25-NDs were administered in an in vitro model of latent HIV and acute T cell leukemia using J-Lat 10.6 cells,the NDs were observed to prime J-Lat cells resulting in significantly increased NK cell-mediated cytotoxicity compared to free prostratin plus anti-CD25,and other controls.These findings demonstrate the feasibility of using our Pro-aCD25-NDs to prime target cells for enhancing the cytotoxicity of NK cells as antiviral or antitumor agents.
基金supported by grants from the National Institutes of Health(AI64350,CA171972,CA58033 and AG036690).
文摘The X-linked Trap1a gene encodes the tumor rejection antigen P1A,which is expressed in fetal tissues and multiple lineages of tumor cells.The function of this gene remains unknown.Using chimeric mice with wild-type(WT)and Trap1a^(−/y)bone marrow,we show that Trap1a^(−/y)donor cells are capable of generating most lineages of hematopoietic cells,with the notable exception of T cells.Deletion of Trap1a selectively arrests T-cell development at double-negative stage 1(DN1,with a CD4^(−)CD8^(−)CD25^(−)CD44^(+)phenotype).Because Trap1a is expressed in Lin^(−)Sca-1^(+)c-Kit^(+)and common lymphoid progenitors but not in immature thymocytes(DN1-DN4),Trap1a mutations affect the differentiation potential of progenitor cells without directly acting on T cells.Despite a similarity in the blockade of DN1 to DN2 transition,the Trap1a^(−/y)DN1 cells have normal expression of c-Kit,in contrast to what was reported in the Notch1^(−/−)DN1.Complementary DNA profiling of Trap1a^(−/y)and WT embryonic stem cells shows that Trap1a does not regulate the Notch pathway.Our data reveal that Trap1a is an X-linked regulator that affects the differentiation potential of progenitor cells into T cells through a Notch-independent mechanism and identify an important function for the Trap1a gene.
文摘Multiple myeloma （MM） remains an incurable neoplastic disease, although high-dose chemotherapy supported by autologous stem cells, and the latest integration of several novel agents, including thalidomide, bortezomib and lenalidomide, into each step of therapeutics have substantially improved the outcome of patients with MM.1-5 Herein, we gave our own considerations on some promising directions in the near future, aiming at further improving the survival and the quality of life of MM patients, and even achieving our final goal of the cure of MM, including highlighting stratified and individualized therapies, pursuing novel targets and strategies, unraveling the biological characteristics of myeloma initiation cells and strengthening post-transplant immunotherapies.
