New Flavors in Immunomodulation

Whether to boost the immune system or to tame it, drugs that modulate immune function are becoming an essential part of modern pharmacopoeia. While many of these target molecules that are expressed by immune cells, recent advances in immunometabolism are now opening new classes of modulators that derive from endogenous metabolites. It is becoming clear that the immune system is involved in many diseases, including conditions that were not traditionally considered infectious, inflammatory, or autoimmune, such as cancer and cardiovascular diseases. In that context, immunomodulation is now a critical part of the pharmaceutic arsenal, either for the potentiation of immune responses, with anti-PD-1 or anti-CTLA-4 as obvious examples, or to limit them, with anti-tumor necrosis factors (TNFs) leading drug sales for the last few years. By and large, research in this area has been focused on blocking immune cytokines and receptors either through antibodies or kinase inhibitors. Now, with two recent studies reporting the use of modified metabolites to suppress immune responses (Kornberg et al., 2018; Mills et al., 2018), immunometabolism is opening a new front in the quest to modulate immune function. Indeed, the current approaches have shown extraordinary success, but they have also sometimes been limited by the redundancy of immune activators and inhibitors. For example, immune exhaustion in cancer is mediated by a large variety of soluble and cell-surface molecules, and despite the success of anti-PD-1 as a single agent, many other receptors might need to be blocked simultaneously to improve therapeutic efficiency further and overcome resistance (Sharma et al., 2017). In addition to immune mediators, the function of immune cells is also modulated by all core pathways for cellular function, and metabolism has emerged as a critical hub in their activation. This line of inquiry started with the observa-