The role of ROS in tumor infiltrating immune cells and cancer immunotherapy.

Reactive oxygen species (ROS) are a group of short-lived highly reactive molecules formed intracellularly from molecular oxygen. ROS can alter biochemical, transcriptional, and epigenetic programs and have an indispensable role in cellular function. In immune cells, ROS are mediators of specialized functions such as phagocytosis, antigen presentation, activation, cytolysis, and differentiation. ROS have a fundamental role in the tumor microenvironment (TME) where they are produced by immune cell-intrinsic and -extrinsic mechanisms. ROS can act as a double-edged sword with short exposures leading to activation in various innate and adaptative immune cells, and prolonged exposures, unopposed by redox balancing antioxidants leading to exhaustion, immunosuppression, and unresponsiveness to cancer immunotherapy. Due to its plasticity and impact on the anti-tumor function of immune cells, attempts are currently in process to harness ROS biology with the purpose to improve contemporary strategies of cancer immunotherapy. Here, we provide a short overview how ROS and various antioxidant systems impact on the function of innate and adaptive immune system cells with emphasis on the TME and immune-based therapies for cancer.

Immune-related adverse effects of checkpoint immunotherapy and implications for the treatment of patients with cancer and autoimmune diseases.

During the past decade, there has been a revolution in cancer therapeutics by the emergence of antibody-based immunotherapies that modulate immune responses against tumors. These therapies have offered treatment options to patients who are no longer responding to classic anti-cancer therapies. By blocking inhibitory signals mediated by surface receptors that are naturally upregulated during activation of antigen-presenting cells (APC) and T cells, predominantly PD-1 and its ligand PD-L1, as well as CTLA-4, such blocking agents have revolutionized cancer treatment. However, breaking these inhibitory signals cannot be selectively targeted to the tumor microenvironment (TME). Since the physiologic role of these inhibitory receptors, known as immune checkpoints (IC) is to maintain peripheral tolerance by preventing the activation of autoreactive immune cells, IC inhibitors (ICI) induce multiple types of immune-related adverse effects (irAEs). These irAEs, together with the natural properties of ICs as gatekeepers of self-tolerance, have precluded the use of ICI in patients with pre-existing autoimmune diseases (ADs). However, currently accumulating data indicates that ICI might be safely administered to such patients. In this review, we discuss mechanisms of well established and newly recognized irAEs and evolving knowledge from the application of ICI therapies in patients with cancer and pre-existing ADs.