NK Cell Dysfunction and Checkpoint Immunotherapy.

Jiacheng Bi,Zhigang Tian

doi:10.3389/fimmu.2019.01999

Abstract

NK cells play important roles in the innate immune responses against tumors. The effector function of NK cells relies on the integration of activating and inhibitory signals. Emerging checkpoint receptors and molecules are being revealed to mediate NK cell dysfunction in the tumor microenvironment. Inhibition of some NK cell surface checkpoint receptors has displayed the potential to reverse NK cell dysfunction in tumors, and to boost anti-tumor immunity, both in clinical trials (anti-KIR and anti-NKG2A), and in preclinical studies (e.g., anti-TIGIT, and anti-CD96). To fully exploit the potential of NK–based checkpoint immunotherapy, more understanding of the regional features of NK cells in the tumor microenvironment is required. This will provide valuable information regarding the dynamic nature of NK cell immune response against tumors, as well as novel checkpoints or pathways to be targeted. In this Review, we discuss recent advances in the understanding of NK cell dysfunction in tumors, as well as emerging strategies of NK-based checkpoint immunotherapy for tumors.

Highlights

Limited response rates of T cell–based checkpoint immunotherapies against CTLA-4 (CytoToxic Lymphocyte Antigen 4) and/or PD-1 (Programmed-cell Death protein 1)/PD-L1 indicate that additional checkpoints/pathways exist to suppress efficient tumor immunity [1,2,3]
AntiPD-1 immunotherapy largely targets T cells, the frequency of intratumoral NK cells was found to correlate with patient responsiveness to PD-1 blockade immunotherapy, and with increased overall survival [31]
Unlike T cells that majorly use antigen-specific T cell receptors (TCR) to recognize target cells for activation, the activation of NK cells relies on the integration of signals from an array of cell surface activating and inhibitory receptors [7, 32, 33]

Summary

NK Cell Dysfunction and Checkpoint Immunotherapy

Reviewed by: Eric Vivier, INSERM U1104 Centre d’immunologie de Marseille-Luminy, France Robin Parihar, Baylor College of Medicine, United States. To fully exploit the potential of NK–based checkpoint immunotherapy, more understanding of the regional features of NK cells in the tumor microenvironment is required. This will provide valuable information regarding the dynamic nature of NK cell immune response against tumors, as well as novel checkpoints or pathways to be targeted. In this Review, we discuss recent advances in the understanding of NK cell dysfunction in tumors, as well as emerging strategies of NK-based checkpoint immunotherapy for tumors

INTRODUCTION

ROLE OF NK CELLS IN TUMOR IMMUNITY

NK CELL ACTIVATION

Findings

NK CELL DYSFUNCTION IN TUMORS