Modulating the wayward T cell: New horizons with immune checkpoint inhibitor treatments in autoimmunity, transplant, and cancer.

Abstract

The T-cell response is regulated by the balance between costimulatory and coinhibitory signals. Immune checkpoints are essential for efficient T-cell activation, but also for maintaining self-tolerance and protecting tissues from damage caused by the immune system, and for providing protective immunity. Modulating immune checkpoints can serve diametric goals, such that blocking a coinhibitory molecule can unleash anti-cancer immunity whereas stimulating the same molecule can reduce an over-reaction in autoimmune disease. The purpose of this review is to examine the regulation of T-cell costimulation and coinhibition, which is central to the processes underpinning autoimmunity, transplant rejection and immune evasion in cancer. We will focus on the immunomodulation agents that regulate these unwanted over- and under-reactions. The use of such agents has led to control of symptoms and slowing of progression in patients with rheumatoid arthritis, reduced rejection rates in transplant patients, and prolonged survival in patients with cancer. The management of immune checkpoint inhibitor treatment in certain challenging patient populations, including patients with pre-existing autoimmune conditions or transplant patients who develop cancer, as well as the management of immune-related adverse events in patients receiving antitumor therapy, is examined. Finally, the future of immune checkpoint inhibitors, including examples of emerging targets that are currently in development, as well as recent insights gained using new molecular techniques, is discussed. T-cell costimulation and coinhibition play vital roles in these diverse therapeutic areas. Targeting immune checkpoints continues to be a powerful avenue for the development of agents suitable for treating autoimmune diseases and cancers and for improving transplant outcomes. Enhanced collaboration between therapy area specialists to share learnings across disciplines will improve our understanding of the opposing effects of treatments for autoimmune disease/transplant rejection versus cancer on immune checkpoints, which has the potential to lead to improved patient outcomes.