Natural killer cells and immune-checkpoint inhibitor therapy: Current knowledge and new challenges

The discovery of immune checkpoints (ICs) and the development of specific blockers to relieve immune effector cells from this inhibiting mechanism has changed the view of anti-cancer therapy. In addition to cytotoxic T lymphocyte antigen 4 (CTLA4) and programmed death 1 (PD1), classical ICs of T lymphocytes and recently described also on a fraction of natural killer (NK) cells, several NK cell receptors, including killer immunoglobulin-like inhibitory receptors (KIRs) and NGK2A, have been recognized as checkpoint members typical of the NK cell population. This offers the opportunity of a dual-checkpoint inhibition approach, targeting classical and non-classical ICs and leading to a synergistic therapeutic effect. In this review, we will overview and discuss this new perspective, focusing on the most relevant candidates for this role among the variety of potential NK ICs. Beside listing and defining classical ICs expressed also by NK cells, or non-classical ICs either on T or on NK cells, we will address their role in NK cell survival, chronic stimulation or functional exhaustion, and the potential relevance of this phenomenon on anti-tumor immune response. Furthermore, NK ICs will be proposed as possible new targets for the development of efficient combined immunotherapy, not forgetting the relevant concerns that may be raised on NK IC blockade. Finally, the impact of epigenetic drugs in such a complex therapeutic picture will be briefly addressed.