Metabolic flexibility has emerged as a critical determinant of CD8+T-cell antitumor activity,yet the mechanisms driving the metabolic flexibility of T cells have not been determined.In this study,we investigated the i...Metabolic flexibility has emerged as a critical determinant of CD8+T-cell antitumor activity,yet the mechanisms driving the metabolic flexibility of T cells have not been determined.In this study,we investigated the influence of the nuclear cap-binding complex(CBC)adaptor protein ARS2 on mature T cells.In doing so,we discovered a novel signaling axis that endows activated CD8+T cells with flexibility of glucose catabolism.ARS2 upregulation driven by CD28 signaling reinforced splicing factor recruitment to pre-mRNAs and affected approximately one-third of T-cell activation-induced alternative splicing events.Among these effects,the CD28-ARS2 axis suppressed the expression of the M1 isoform of pyruvate kinase in favor of PKM2,a key determinant of CD8+T-cell glucose utilization,interferon gamma production,and antitumor effector function.Importantly,PKM alternative splicing occurred independently of CD28-driven PI3K pathway activation,revealing a novel means by which costimulation reprograms glucose metabolism in CD8+T cells.展开更多
The genetic alterations associated with cell transformation are in large measure expressed in the metabolic phenotype as cancer cells proliferate and change their local environment,and prepare for metastasis.Qualitati...The genetic alterations associated with cell transformation are in large measure expressed in the metabolic phenotype as cancer cells proliferate and change their local environment,and prepare for metastasis.Qualitatively,the fundamental biochemistry of cancer cells is generally the same as in the untransformed cells,but the cancer cells produce a local environment,the TME,that is hostile to the stromal cells,and compete for nutrients.In order to proliferate,cells need sufficient nutrients,either those that cannot be made by the cells themselves,or must be made from simpler precursors.However,in solid tumors,the nutrient supply is often limiting given the potential for rapid proliferation,and the poor quality of the vasculature.Thus,cancer cells may employ a variety of strategies to obtain nutrients for survival,growth and metastasis.Although much has been learned using established cell lines in standard culture conditions,it is becoming clear from in vivo metabolic studies that this can also be misleading,and which nutrients are used for energy production versus building blocks for synthesis of macromolecules can vary greatly from tumor to tumor,and even within the same tumor.Here we review the operation of metabolic networks,and how recent understanding of nutrient supply in the TME and utilization are being revealed using stable isotope tracers in vivo as well as in vitro.展开更多
基金supported by National Cancer Institute grants R00CA175189,R01AI155499(both to SHO),R01CA205246(to EAR),R01CA121044(to KPL),T32CA085183(to GAH and MML),and P30CA016056,involving the use of the Roswell Park Comprehensive Cancer Center Flow and Image Cytometry,Genomics,Laboratory Animal,and Immune Analysis Shared Resourcesby the Roswell Park Alliance Foundation.NMR experiments were carried out at the Center for Environmental and Systems Biochemistry Shared Resource Facility funded in part by the Markey Cancer Center(P30CA177558).
文摘Metabolic flexibility has emerged as a critical determinant of CD8+T-cell antitumor activity,yet the mechanisms driving the metabolic flexibility of T cells have not been determined.In this study,we investigated the influence of the nuclear cap-binding complex(CBC)adaptor protein ARS2 on mature T cells.In doing so,we discovered a novel signaling axis that endows activated CD8+T cells with flexibility of glucose catabolism.ARS2 upregulation driven by CD28 signaling reinforced splicing factor recruitment to pre-mRNAs and affected approximately one-third of T-cell activation-induced alternative splicing events.Among these effects,the CD28-ARS2 axis suppressed the expression of the M1 isoform of pyruvate kinase in favor of PKM2,a key determinant of CD8+T-cell glucose utilization,interferon gamma production,and antitumor effector function.Importantly,PKM alternative splicing occurred independently of CD28-driven PI3K pathway activation,revealing a novel means by which costimulation reprograms glucose metabolism in CD8+T cells.
基金This work was supported in part by the Carmen L Buck Chair in Oncology(to ANL)the Edith D.Gardner Chair in Cancer Research(to TWMF)and funding from NIH 1P01CA163223-01A1,5P20GM121327 and P30CA177558.
文摘The genetic alterations associated with cell transformation are in large measure expressed in the metabolic phenotype as cancer cells proliferate and change their local environment,and prepare for metastasis.Qualitatively,the fundamental biochemistry of cancer cells is generally the same as in the untransformed cells,but the cancer cells produce a local environment,the TME,that is hostile to the stromal cells,and compete for nutrients.In order to proliferate,cells need sufficient nutrients,either those that cannot be made by the cells themselves,or must be made from simpler precursors.However,in solid tumors,the nutrient supply is often limiting given the potential for rapid proliferation,and the poor quality of the vasculature.Thus,cancer cells may employ a variety of strategies to obtain nutrients for survival,growth and metastasis.Although much has been learned using established cell lines in standard culture conditions,it is becoming clear from in vivo metabolic studies that this can also be misleading,and which nutrients are used for energy production versus building blocks for synthesis of macromolecules can vary greatly from tumor to tumor,and even within the same tumor.Here we review the operation of metabolic networks,and how recent understanding of nutrient supply in the TME and utilization are being revealed using stable isotope tracers in vivo as well as in vitro.
