Regulation of PD-L1 expression on cancer cells with ROS-modulating drugs

Monoclonal antibodies targeting the programmed-death 1 (PD-1) immune checkpoint or its ligand PD-L1 have significantly improved the treatment of cancers but more efficient drugs and combinations are still needed to increase the therapeutic efficacy. As the oxidative state of the immune microenvironment plays a critical role in the antitumor immune response, it is important to evaluate the impact of molecules and drugs used for oxidative stress control on PD-L1 expression and functions. Here we have reviewed the functional relationship between reactive oxygen species (ROS) and PD-L1 expressed on cancer cells, and analyzed the effects of 15 pharmacological ROS modulators - both ROS inducers and attenuators - on PD-L1 expression. The interplay between tumor hypoxia, the HIF-1α/YAP1/NFκB signaling routes and PD-L1 expression has been analyzed and specific non-cytotoxic ROS-associated drugs known to modulate this system are discussed. A complex interplay between ROS effectors and PD-L1 expression is revealed, showing that depending on their targets and mechanisms, ROS effectors can engender an up or down-regulation of PD-L1 expression in cancer cells. An enhanced generation of ROS often promotes PD-L1 expression and, conversely, ROS scavenging generally represses PD-L1. But there are noticeable exceptions with drugs that augment ROS production while reducing PD-L1 expression and vice versa. The variable PD-L1 response to ROS modulation reflects the complexity of ROS biology in the tumor microenvironment. A deeper knowledge of the contribution of ROS to PD-(L)1 immune checkpoint control is warranted.