Nicotinamide Inhibits T Cell Exhaustion and Increases Differentiation of CD8 Effector T Cells

Simple Summary T cells that undergo repeated stimulation undergo a change called T cell exhaustion (TEx) that limits their ability to kill cancer cells and infections with microorganisms. The factors involved in the initiation and kinetics of these changes are poorly understood. In this research the authors have used an in-vitro model of repeated stimulation to investigate whether changes of TEx can be prevented by providing nicotinamide that is known to be integral in energy supply to cells. The model was found to be a good replicate of TEx changes such as upregulation of inhibitory receptors and down regulation of cytokines involved in killing of cancer. The results provide strong support for the notion that TEx results from poor energy supply from mitochondria due to generation of reactive oxygen species and that these changes can be prevented and reversed by treatment with nicotinamide. These findings appear to have important implications for treatment of cancers by immunotherapy. One of the limitations of immunotherapy is the development of a state referred to as T cell exhaustion (TEx) whereby T cells express inhibitory receptors (IRs) and lose production of effectors involved in killing of their targets. In the present studies we have used the repeated stimulation model with anti CD3 and anti CD28 to understand the factors involved in TEx development and treatments that may reduce changes of TEx. The results show that addition of nicotinamide (NAM) involved in energy supply to cells prevented the development of inhibitory receptors (IRs). This was particularly evident for the IRs CD39, TIM3, and to a lesser extent LAG3 and PD1 expression. NAM also prevented the inhibition of IL-2 and TNF alpha expression in TEx and induced differentiation of CD4+ and CD8 T cells to effector memory and terminal effector T cells. The present results showed that effects of NAM were linked to regulation of reactive oxygen species (ROS) consistent with previous studies implicating ROS in upregulation of TOX transcription factors that induce TEx. These effects of NAM in reducing changes of TEx and in increasing the differentiation of T cells to effector states appears to have important implications for the use of NAM supplements in immunotherapy against cancers and viral infections and require further exploration in vivo.