Lack of Bcl6 promotes anti-tumor immunity by activating glycolysis to rescue CD8 T cell function
Nemazee, D.; Luan, F.; Li, Y.; Ning, J.; Tran, J. T.; Blane, T.; Bhargava, R.; Huang, Z.; Xiao, C.
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T cells are one of the most powerful weapons to fight cancer; however, T cell exhaustion and dysfunction restrict their long-lasting function in anti-tumor immunity. B-cell lymphoma 6 (BCL6) has many functions in CD8 T cells but it is unclear how it regulates the effector function and exhaustion of CD8 cells. Overall, a low level of BCL6 mRNA in human cancer samples is associated with better outcomes. We found that BCL6 deficiency in activated CD8 T cells enhanced tumor repression in multiple mouse models. More IL-2-expressing CD8 T cells and reduced proportions of exhausted or dysfunctional CD8 T cells were detected within tumors when Bcl6 was knocked out upon T cell activation. Glycolysis was promoted in BCL6-deficient CD8 T cells owing to derepression of glucose transporter GLUT3 (encoded by Slc2a3). The BCL6 inhibitor Fx1 promoted anti-tumor immunity in a T cell-dependent manner. These findings suggest a novel pathway to restore effector function of CD8 T cells by changing their energy utilization pathways to facilitate long-term tumor resistance. Summary BlurbBCL6 limits CD8 T cell responses to tumors by inhibiting Glut3 expression. Conditional deletion of Bcl6 in activated CD8 T cells or pharmacological inhibition of BCL6 in mice represses tumor growth.
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