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Review ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Immunol. | doi: 10.3389/fimmu.2019.02354

The rise of NK cell checkpoint inhibitors as promising therapeutic targets in cancer immunotherapy

 Cheng Sun1, 2, 3* and  Haoyu Sun2, 3*
  • 1Department of Life Sciences and Medicine, The First Affiliated Hospital, University of Science and Technology of China, China
  • 2Division of Molecular Medicine, Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, China
  • 3Institute of Immunology, University of Science and Technology of China, China

Checkpoint immunotherapy that targets inhibitory receptors of T cells, thereby reversing the functional exhaustion of T cells, marks a breakthrough in anticancer therapy. The success of T cell-directed checkpoint inhibitors of CTLA-4 and PD-1 has opened a new approach for cancer immunotherapy and resulted in extensive research on immune checkpoints. However, it is only in recent years that research on NK cell exhaustion and potential checkpoints impacting NK cells has become popular. NK cells, as the major player in innate immunity, are critical for immune surveillance, particularly the control of metastasis and hematological cancers. The balance between activating and inhibitory signals fine tunes the activation and effector functions of NK cells, and transformed cells modulate NK cells by upregulating negative signaling that “exhausts” NK cells. Exhausted NK cells with excessive expression of inhibitory receptors (checkpoint molecules) are impaired in the recognition of tumor cells as well as antitumor cytotoxicity and cytokine secretion. Therefore, an understanding of the potential checkpoint molecules involved in NK cell exhaustion is particularly important in terms of NK cell-targeted cancer immunotherapy. In this review, we summarize recent advances in NK cell checkpoint inhibitors and their progress in clinical trials. Moreover, we highlight some of the latest findings in fundamental NK cell receptor biology and propose potential NK cell checkpoint molecules for future immunotherapeutic applications.

Keywords: NK cell, NK cell exhaustion, Inhibitory Receptor, Checkpoint inhibitor, cancer immunotherapy

Received: 14 Jul 2019; Accepted: 18 Sep 2019.

Copyright: © 2019 Sun and Sun. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Dr. Cheng Sun, Department of Life Sciences and Medicine, The First Affiliated Hospital, University of Science and Technology of China, Hefei, Anhui Province, China, charless@ustc.edu.cn
Dr. Haoyu Sun, Division of Molecular Medicine, Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei, 230026, Anhui Province, China, haoyusun@ustc.edu.cn