Aberrant expression of Myc is one of the most common oncogenic events in human cancers.Scores of Myc inhibitors are currently under development for treating Myc-driven cancers.In addition to directly targeting tumor c...Aberrant expression of Myc is one of the most common oncogenic events in human cancers.Scores of Myc inhibitors are currently under development for treating Myc-driven cancers.In addition to directly targeting tumor cells,Myc inhibition has been shown to modulate the tumor microenvironment to promote tumor regression.However,the effect of Myc inhibition on immune cells in the tumor microenvironment remains poorly understood.Here,we show that the adaptive immune system plays a vital role in the antitumor effect of pharmacologic inhibition of Myc.Combining genetic and pharmacologic approaches,we found that Myc inhibition enhanced CD8 T cell function by suppressing the homeostasis of regulatory T(Treg)cells and the differentiation of resting Treg(rTreg)cells to activated Treg(aTreg)cells in tumors.Importantly,we demonstrated that different Myc expression levels confer differential sensitivity of T cell subsets to pharmacologic inhibition of Myc.Although ablation of the Myc gene has been shown to suppress CD8 T cell function,Treg cells,which express much less Myc protein than CD8 T cells,are more sensitive to Myc inhibitors.The differential sensitivity of CD8 T and Treg cells to Myc inhibitors resulted in enhanced CD8 T cell function upon Myc inhibition.Our findings revealed that Myc inhibitors can induce an antitumor immune response during tumor progression.展开更多
Cellular immunity mediated by CD8+T cells plays an indispensable role in bacterial and viral clearance and cancers.However,persistent antigen stimulation of CD8+T cells leads to an exhausted or dysfunctional cellular ...Cellular immunity mediated by CD8+T cells plays an indispensable role in bacterial and viral clearance and cancers.However,persistent antigen stimulation of CD8+T cells leads to an exhausted or dysfunctional cellular state characterized by the loss of effector function and high expression of inhibitory receptors during chronic viral infection and in tumors.Numerous studies have shown that glycogen synthase kinase 3(GSK3)controls the function and development of immune cells,but whether GSK3 affects CD8+T cells is not clearly elucidated.Here,we demonstrate that mice with deletion of Gsk3αand Gsk3βin activated CD8+T cells(DKO)exhibited decreased CTL differentiation and effector function during acute and chronic viral infection.In addition,DKO mice failed to control tumor growth due to the upregulated expression of inhibitory receptors and augmented T-cell exhaustion in tumor-infiltrating CD8+T cells.Strikingly,anti-PD-1 immunotherapy substantially restored tumor rejection in DKO mice.Mechanistically,GSK3 regulates T-cell exhaustion by suppressing TCR-induced nuclear import of NFAT,thereby in turn dampening NFAT-mediated exhaustion-related gene expression,including TOX/TOX2 and PD-1.Thus,we uncovered the molecular mechanisms underlying GSK3 regulation of CTL differentiation and T-cell exhaustion in anti-tumor immune responses.展开更多
基金This study was supported by the National Natural Science Foundation of China(31770953,81830047,81961138008 to CX,32070877 to W-HL,and 31570883 to NX)1000 Young Talents Program of China(NX)the Fundamental Research Funds for the Central Universities of China-Xiamen University(20720170064 to CX).
文摘Aberrant expression of Myc is one of the most common oncogenic events in human cancers.Scores of Myc inhibitors are currently under development for treating Myc-driven cancers.In addition to directly targeting tumor cells,Myc inhibition has been shown to modulate the tumor microenvironment to promote tumor regression.However,the effect of Myc inhibition on immune cells in the tumor microenvironment remains poorly understood.Here,we show that the adaptive immune system plays a vital role in the antitumor effect of pharmacologic inhibition of Myc.Combining genetic and pharmacologic approaches,we found that Myc inhibition enhanced CD8 T cell function by suppressing the homeostasis of regulatory T(Treg)cells and the differentiation of resting Treg(rTreg)cells to activated Treg(aTreg)cells in tumors.Importantly,we demonstrated that different Myc expression levels confer differential sensitivity of T cell subsets to pharmacologic inhibition of Myc.Although ablation of the Myc gene has been shown to suppress CD8 T cell function,Treg cells,which express much less Myc protein than CD8 T cells,are more sensitive to Myc inhibitors.The differential sensitivity of CD8 T and Treg cells to Myc inhibitors resulted in enhanced CD8 T cell function upon Myc inhibition.Our findings revealed that Myc inhibitors can induce an antitumor immune response during tumor progression.
基金supported by the National Natural Science Foundation of China(31770953,81830047,and 81961138008 to CX and 32070877 to W-HL),1000 Young Talents Program of China(NX)the Fundamental Research Funds for the Central Universities of China-Xiamen University(20720170064 to CX).
文摘Cellular immunity mediated by CD8+T cells plays an indispensable role in bacterial and viral clearance and cancers.However,persistent antigen stimulation of CD8+T cells leads to an exhausted or dysfunctional cellular state characterized by the loss of effector function and high expression of inhibitory receptors during chronic viral infection and in tumors.Numerous studies have shown that glycogen synthase kinase 3(GSK3)controls the function and development of immune cells,but whether GSK3 affects CD8+T cells is not clearly elucidated.Here,we demonstrate that mice with deletion of Gsk3αand Gsk3βin activated CD8+T cells(DKO)exhibited decreased CTL differentiation and effector function during acute and chronic viral infection.In addition,DKO mice failed to control tumor growth due to the upregulated expression of inhibitory receptors and augmented T-cell exhaustion in tumor-infiltrating CD8+T cells.Strikingly,anti-PD-1 immunotherapy substantially restored tumor rejection in DKO mice.Mechanistically,GSK3 regulates T-cell exhaustion by suppressing TCR-induced nuclear import of NFAT,thereby in turn dampening NFAT-mediated exhaustion-related gene expression,including TOX/TOX2 and PD-1.Thus,we uncovered the molecular mechanisms underlying GSK3 regulation of CTL differentiation and T-cell exhaustion in anti-tumor immune responses.
