Abstract
Simple SummaryT 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 TNFα 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.
Highlights
IntroductionOn T cells has been a major advance in treatment of cancers such as melanoma and lung cancer and is considered to be the standard of care
The introduction of immunotherapy based on immune checkpoint blockade (ICB)on T cells has been a major advance in treatment of cancers such as melanoma and lung cancer and is considered to be the standard of care
Downregulation of the inhibitory receptors (IRs) by NAM was consistent across four biological repeats, from independent experiments as shown by Figure 1C where the CD8+ T cell data from days five, seven, and nine has been normalized as fold change relative to untreated cultures, from the equivalent day in order to account for marker expression differences between donors
Summary
On T cells has been a major advance in treatment of cancers such as melanoma and lung cancer and is considered to be the standard of care. Limitations of these treatments are the relatively high rates of primary and acquired resistance to these treatments. Multiple causes of resistance to immunotherapy have been defined [1,2,3] including defects in antigen presentation [4] and low T cell infiltration into tumors [5]. Recent single cell studies in melanoma have shown that TEx changes are evident on high affinity CD8 T cells against neoantigens and potentially a major limitation on the effectiveness of immunotherapy in melanoma [10]. The extent to which TEx is due to epigenetic changes has received much attention in a number of studies [11,12,13,14,15]
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