Control of NK Cell Activation by Immune Checkpoint Molecules.

Asma Beldi-Ferchiou,Sophie Caillat-Zucman

doi:10.3390/ijms18102129

Abstract

The development of cancer and chronic infections is facilitated by many subversion mechanisms, among which enhanced expression of immune checkpoints molecules, such as programmed death-1 (PD-1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), on exhausted T cells. Recently, immune checkpoint inhibitors have shown remarkable efficiency in the treatment of a number of cancers. However, expression of immune checkpoints on natural killer (NK) cells and its functional consequences on NK cell effector functions are much less explored. In this review, we focus on the current knowledge on expression of various immune checkpoints in NK cells, how it can alter NK cell-mediated cytotoxicity and cytokine production. Dissecting the role of these inhibitory mechanisms in NK cells is critical for the full understanding of the mode of action of immunotherapies using checkpoint inhibitors in the treatment of cancers and chronic infections.

Highlights

Natural killer (NK) cells are key players in the elimination of cells that have undergone infection, malignant transformation, or even physical or chemical damage [1,2,3,4,5]
We focus on the current state of the art on expression of immune checkpoint molecules on NK cells and how it can interfere with NK cell functions
A strategy to further improve rituximab responses is the use of killer cell Ig-like receptors (KIRs) blockade therapy, which releases NK cells from the inhibition exerted by the high level of major histocompatibility complex (MHC)-I expression on tumor cells

Summary

Introduction

Natural killer (NK) cells are key players in the elimination of cells that have undergone infection, malignant transformation, or even physical or chemical damage [1,2,3,4,5]. Integration of all signals transmitted by these receptors tightly regulates NK-cell behavior and determines the magnitude of NK-cell-mediated cytotoxicity and cytokine production [7,8,9] Inhibitory receptors such as killer cell Ig-like receptors (KIRs) and natural killer cell receptor group 2 member A CD94/NKG2A heterodimer recognize major histocompatibility complex (MHC) class I molecules. The development of chronic infections and cancers is facilitated by various immune subversion mechanisms targeting NK cell effector functions, such as the production of regulatory cytokines or immunosuppressive factors, decreased expression of activating receptors or their ligands, and expression of immune checkpoint molecules [29,30,31,32,33,34].

Programmed Cell Death-1

Findings

Concluding Remarks