At the crossroad between antitumor immunity and cancer metabolism: PD-L1 modulation by NAD+ and mTOR

mTOR signaling, glutamine and NAD metabolism have all a crucial role in cancer onset and progression. Therefore, specific anticancer strategies have been designed to inhibit the key components of each one these cellular pathways. Disappointingly, clinical data did not meet the expectations, and only a limited subset of patients has benefitted from the individual inhibition of either pathway, owing to the tremendous metabolic and genetic plasticity of cancer cells that enables the activation of resistance mechanisms. Programmed cell death protein 1 (PD-1) and its ligand PD-L1 play an important suppressive role in the immune system and the latest advances in immunotherapies have brought to the development of several anti PD-1 or anti PD-L1 antibodies capable of unleashing the patients’ anti-tumor immunity. However, the efficacy of these “immune checkpoint inhibitors (ICI)” varies according to the cancer type, and even within patients affected by the same type of malignancy. In particular, one of the main challenges remains the identification of reliable prospective biomarkers capable of identifying patients that are more likely to benefit from ICI. In this assay, I present emerging links between PD-L1 expression and cancer metabolism. Remarkably, mTOR signaling, glutamine and NAD metabolism have all been found to modulate PD-L1 expression via different mechanisms, indicating that pharmacological manipulation of key metabolic pathways in tumors has also dramatic consequences on the immune system and anti-cancer immune responses. These new connections that until recently have been overlooked, could be used in the near future to sensitize cancer cells to PD-1/PD-L1 checkpoint inhibition. Thus, these findings may pave the way to the development of novel anticancer strategies that tackle the tumor from different angles by combining targeted therapies and immunotherapy, with the hope to overcome the drawbacks of individual therapeutic approaches.