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

Yuqing Cao,Chaoliu Dai,Yu Tian,Rui Song,Crystal Widarma,Feng Xu,Xiaoyu Wang,Tianqiang Jin

doi:10.1038/s41392-020-00348-8

Abstract

Recent studies have demonstrated the potential of natural killer (NK) cells in immunotherapy to treat multiple types of cancer. NK cells are innate lymphoid cells that play essential roles in tumor surveillance and control that efficiently kill the tumor and do not require the major histocompatibility complex. The discovery of the NK’s potential as a promising therapeutic target for cancer is a relief to oncologists as they face the challenge of increased chemo-resistant cancers. NK cells show great potential against solid and hematologic tumors and have progressively shown promise as a therapeutic target for cancer immunotherapy. The effector role of these cells is reliant on the balance of inhibitory and activating signals. Understanding the role of various immune checkpoint molecules in the exhaustion and impairment of NK cells when their inhibitory receptors are excessively expressed is particularly important in cancer immunotherapy studies and clinical implementation. Emerging immune checkpoint receptors and molecules have been found to mediate NK cell dysfunction in the tumor microenvironment; this has brought up the need to explore further additional NK cell-related immune checkpoints that may be exploited to enhance the immune response to refractory cancers. Accordingly, this review will focus on the recent findings concerning the roles of immune checkpoint molecules and receptors in the regulation of NK cell function, as well as their potential application in tumor immunotherapy.

Highlights

Natural killer (NK) cells are cytotoxic lymphocytes in the family of innate lymphoid cells that play essential roles in the first line of defense against cancer and viral infections.[1,2,3] Human NK cells make up to 15 percent of the circulating lymphocytes and are associated with the killing and destruction of microbially infected and malignantly autologous and allogenic cells.[4]NK cells have been determined to demonstrate antitumor cell cytotoxicity in the absence of prior sensitization and the subsequent production of cytokines alongside chemokines that have an effect on regulating certain immune responses.[4]
More researches have shown that the blockade of checkpoint inhibitory receptors may be crucial in effectively reversing T cell exhaustion and the restoration of the antitumor capacity of T cells,[15] there has been growing interest in the immune effects these treatments may have on NK cells as well
The immunosuppressive role of NK cells, combination strategies rationally targeting the pathway with adoptive cell therapies (ACT), and checkpoint inhibitors can synergistically promote the function of antitumor immune cell function, a process that utilizes ATP generated in the tumor microenvironment (TME) (Fig. 4) (Table 3).[271,299,300]

Summary

1234567890();,: INTRODUCTION

Natural killer (NK) cells are cytotoxic lymphocytes in the family of innate lymphoid cells that play essential roles in the first line of defense against cancer and viral infections.[1,2,3] Human NK cells make up to 15 percent of the circulating lymphocytes and are associated with the killing and destruction of microbially infected and malignantly autologous and allogenic cells.[4]. LAG-3 is similar to CD4, yet it manifests a higher binding affinity to MHC class II molecules than CD4 It is expressed on activated T cells and NK cells.[174] Another of its potential ligand is LSECtin, a member of the DCSIGN family.[175,176] There is a high tion, a concept through which pathways such as the TIM-3 pathway sometimes regulate immune responses’ distinct features; expression of LAG-3 in patients with Hodgkin lymphoma, acute myelocytic leukemia, and chronic lymphocytic leukemia.[177,178,179] Its some other tissues in a patient with the neck cancer can remain unaffected by the targeting.[134,156,157] cytoplasmic tail is made up of three unique and conserved regions in mice and humans. Immune evasion via PD-1/PD-L1 in NK cells and monocytes/ macrophages is prominent in Hodgkin’s lymphoma.[38,77,93,234,235,236,237] one of the immune checkpoint molecules that have already been employed in specific preclinical tumor models is the establishment of efficacy in blocking TIGIT to modulate NK cell function and has resulted in improved clinical responses in patients with cancer.[7,94,95]

Key results

LIMITATIONS

Findings

CONCLUSION