The biology of PD1 and CTLA-4 as immunotherapeutic targets and the issue of biomarkers

Abstract

The identification in the 1990's of the role of CTLA-4 and PD-1, two inhibitory receptors of T lymphocytes, in the control of the anti-tumor immune responses, led to the awarding of the Nobel Prize in Physiology or Medicine in 2018 to Dr. James Allison and Dr. Tasuku Honjo. These inhibitory receptors called immune checkpoints are essential to prevent any deleterious impact of on-going immune responses against pathogens or cancer cells on healthy tissues and, hence, guarantee the integrity of the host. These major discoveries have led James Allison and Tasuku Honjo to develop anti-CTLA-4 and anti- PD1/L-1 antibodies, respectively, in order to switch off these immune "brakes", making it possible to efficiently attack tumor cells. CTLA-4 regulates the amplitude of the early T-cell activation and inhibits the activity of CD28, a major activating co-receptor expressed by T cells. PD-1 is expressed by memory and effector T lymphocytes and is involved in the regulation of chronically activated cells, as observed during inflammatory processes. Immunotherapeutic treatments resulting from these discoveries have now a major place in the arsenal of anti-cancer therapies. This review presents firstly a synthesis of knowledge on CTLA-4, PD-1 and their ligands, their mechanisms of action and regulation and, secondly, an overview of biomarkers that have been associated with clinical response to anti-PD-1/PD-L1 and anti-CTLA-4 antibody therapies.