The ability of T-cells to control tumor growth is limited by the loss of proliferative capacity within the tumor microenvironment, but the mechanisms by which this occurs have remained unclear. I will discuss how chronic antigenic stimulation-dependent reprogramming of T-cell metabolism drives terminal T-cell dysfunction and limits response to immune checkpoint blockade. Chronic T-cell stimulation-driven impairment of ADP-coupled oxidative phosphorylation is necessary and sufficient to restrict T-cell self-renewal and activate an exhaustion-associated gene expression program. Understanding how shifts in metabolic behavior govern T-cell fate decisions will enable development of novel strategies to enhance the depth and durability of anti-tumor immune responses.
(Refreshments will be served at 2:45 pm)