The role of the transcription factor NF-κB in shaping the cancer microenvironment is becoming increasingly clear. Inflammation alters the activity of enzymes that modulate NF-κB function, and causes extensive change...The role of the transcription factor NF-κB in shaping the cancer microenvironment is becoming increasingly clear. Inflammation alters the activity of enzymes that modulate NF-κB function, and causes extensive changes in genomic chromatin that ultimately drastically alter cell-specific gene expression. NF-κB regulates the expression of cytokines and adhesion factors that control interactions among adjacent cells. As such, NF-κB fine tunes tissue cellular composition, as well as tissues' interactions with the immune system. Therefore, NF-κB changes the cell response to hormones and to contact with neighboring cells. Activating NF-κB confers transcriptional and phenotypic plasticity to a cell and thereby enables profound local changes in tissue function and composition. Research suggests that the regulation of NF-κB target genes is specifically altered in cancer. Such alterations occur not only due to mutations of NF-κB regulatory proteins, but also because of changes in the activity of specific proteostatic modules and metabolic pathways. This article describes the molecular mode of NF-κB regulation with a few characteristic examples of target genes.展开更多
CD28 and 4-1BB costimulatory endodomains included in chimeric antigen receptor(CAR)molecules play a critical role in promoting sustained antitumor activity of CAR-T cells.However,the molecular events associated with t...CD28 and 4-1BB costimulatory endodomains included in chimeric antigen receptor(CAR)molecules play a critical role in promoting sustained antitumor activity of CAR-T cells.However,the molecular events associated with the ectopic and constitutive display of either CD28 or 4-1BB in CAR-T cells have been only partially explored.In the current study,we demonstrated that 4-1BB incorporated within the CAR leads to cell cluster formation and cell death in the forms of both apoptosis and necroptosis in the absence of CAR tonic signaling.Mechanistic studies illustrate that 4-1BB sequesters A20 to the cell membrane in a TRAF-dependent manner causing A20 functional deficiency that in turn leads to NF-κB hyperactivity,cell aggregation via ICAM-1 overexpression,and cell death including necroptosis via RIPK1/RIPK3/MLKL pathway.Genetic modulations obtained by either overexpressing A20 or releasing A20 from 4-1BB by deleting the TRAF-binding motifs of 4-1BB rescue cell cluster formation and cell death and enhance the antitumor ability of 4-1BB-costimulated CAR-T cells.展开更多
文摘The role of the transcription factor NF-κB in shaping the cancer microenvironment is becoming increasingly clear. Inflammation alters the activity of enzymes that modulate NF-κB function, and causes extensive changes in genomic chromatin that ultimately drastically alter cell-specific gene expression. NF-κB regulates the expression of cytokines and adhesion factors that control interactions among adjacent cells. As such, NF-κB fine tunes tissue cellular composition, as well as tissues' interactions with the immune system. Therefore, NF-κB changes the cell response to hormones and to contact with neighboring cells. Activating NF-κB confers transcriptional and phenotypic plasticity to a cell and thereby enables profound local changes in tissue function and composition. Research suggests that the regulation of NF-κB target genes is specifically altered in cancer. Such alterations occur not only due to mutations of NF-κB regulatory proteins, but also because of changes in the activity of specific proteostatic modules and metabolic pathways. This article describes the molecular mode of NF-κB regulation with a few characteristic examples of target genes.
基金P30CA016086NIH S10 Shared Instrumentation Grant,S10OD026951,for supporting this work.
文摘CD28 and 4-1BB costimulatory endodomains included in chimeric antigen receptor(CAR)molecules play a critical role in promoting sustained antitumor activity of CAR-T cells.However,the molecular events associated with the ectopic and constitutive display of either CD28 or 4-1BB in CAR-T cells have been only partially explored.In the current study,we demonstrated that 4-1BB incorporated within the CAR leads to cell cluster formation and cell death in the forms of both apoptosis and necroptosis in the absence of CAR tonic signaling.Mechanistic studies illustrate that 4-1BB sequesters A20 to the cell membrane in a TRAF-dependent manner causing A20 functional deficiency that in turn leads to NF-κB hyperactivity,cell aggregation via ICAM-1 overexpression,and cell death including necroptosis via RIPK1/RIPK3/MLKL pathway.Genetic modulations obtained by either overexpressing A20 or releasing A20 from 4-1BB by deleting the TRAF-binding motifs of 4-1BB rescue cell cluster formation and cell death and enhance the antitumor ability of 4-1BB-costimulated CAR-T cells.
