The Rise of NK Cell Checkpoints as Promising Therapeutic Targets in Cancer Immunotherapy

Abstract

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/PD-L1 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.

NK Cell-Based Immunotherapy in Renal Cell Carcinoma

“…Immune checkpoint inhibitors provide a blockade of inhibitory receptors [94]. PD-1 (programmed cell death protein 1) is expressed in activated T cells and NK cells [95], and along with its ligand PD-L1, has a central role in tumor recurrence and progression, since signaling through this pathway suppresses lymphocytes, including NK cells [80,95].…”

“…Other checkpoints that are mostly expressed in NK cells include, among others, KIR, CD94/NKG2A, and TIGIT [14,19,64,99,100]. Preclinical studies and clinical trials are currently studying the efficacy of the blockade of these checkpoints [94]. For example, anti-KIR mAbs increase tumor cell lysis mediated by NK cells and enhance ADCC in vitro [101,102].…”

“…For example, anti-KIR mAbs increase tumor cell lysis mediated by NK cells and enhance ADCC in vitro [101,102]. Also, there are several clinical trials in phase I/II that have been completed or are still recruiting patients with anti-KIR mAbs, alone or in combination with other checkpoint inhibitors [94,[103][104][105][106]. Related to CD94/NKG2A, it has been demonstrated that blocking its expression by means of a single-chain variable fragment derived from an anti-NKG2A Ab linked to endoplasmic reticulum retention domains overcomes (HLA-E+) tumor resistance to NK cells [107].…”

“…Tumor-associated NK cells also exhibit high expression levels of the checkpoint inhibitory receptor TIGIT, and mAb-mediated blockade of this receptor prevents NK cell exhaustion and elicits potent anti-tumor immunity [109]. Several clinical trials are going on, testing the safety and efficacy of anti-TIGIT mAbs alone or in combination with other mAbs [94].…”

Immune checkpoint molecules in natural killer cells as potential targets for cancer immunotherapy

“… 19 – 22 For example, activating and inhibitory KIR receptors serve to control the development and function of NK cell immunity while adjusting to the tumor microenvironment (TME). 23 , 24 The interactions between KIRs and the corresponding HLA class I ligands contribute to the mediation of NK cell self-tolerance or cytotoxicity against the transformed cells. 24 , 25 The control of unwanted damage of healthy cells by the NK cells is regulated by HLA-class I-specific receptors, which contain a fail-safe mechanism.…”