Abstract
Checkpoint blockade therapy, for example using antibodies against CTLA-4 and PD-1/PD-L1, relieves T cells from the suppression by inhibitory checkpoints in the tumor microenvironment; thereby achieving good outcomes in the treatment of different cancer types. Like T cells, natural killer (NK) cell inhibitory receptors function as checkpoints for NK cell activation. Upon interaction with their cognate ligands on infected cells, tumor cells, dendritic cells and regulatory T cells, signals from these receptors severely affect NK cells' activation and effector functions, resulting in NK cell exhaustion. Checkpoint inhibition with antagonistic antibodies (Abs) can rescue NK cell exhaustion and arouse their robust anti-tumor capacity. Most notably, the response to anti-PD-1 therapy can be enhanced by the increased frequency and activation of NK cells, thereby increasing the overall survival of patients with multiple types of cancer. In addition, rescue of NK cell activity could enhance adaptive T cells' anti-tumor activity. Some antagonistic Abs (e.g., anti-TIGIT and anti-NKG2A monoclonal Abs) have extraordinary potential in cancer therapy, as evidenced by their induction of potent anti-tumor immunity through recovering both NK and T cell function. In this review, we summarize the dysfunction of NK cells in the tumor microenvironment and the key NK cell checkpoint receptors or molecules that control NK cell function. We particularly focus on recent advances in the most promising strategies through blockade of NK cell checkpoints or their combination with other approaches to more effectively reject tumors.
Highlights
In the past few years, cancer immunotherapy has shown great promise
We summarize the dysfunction of natural killer (NK) cells in the tumor microenvironment (TME) and the key NK cell checkpoint receptors or molecules that control NK cell function
We focus on recent advances in the most promising strategies for therapy, such as NK cell checkpoint blockade or its combination with other approaches to more effectively reject tumors
Summary
In the past few years, cancer immunotherapy has shown great promise. Among the most promising therapeutic modalities, chimeric antigen receptor T cell (CAR-T) and immune checkpoint blockade therapies have demonstrated unprecedented clinical success and represent a turning point in cancer treatment. Antigen-presenting cells (APCs), Tregs, and MDSCs in the TME express high levels of PD-L1 and other ligands of immune checkpoint molecules, which prevent NK cell activation, even resulting in NK cell dysfunction or exhaustion [23]. FGL1 shows high expression on human cancer cells, and inhibits the antigen-specific T cell response, while blockade of the LAG-3–FGL1 interaction using antibodies enhanced its anti-tumor effects [86]. Blockade of LAG-3 alone seemed to have no effect on NK cell lysis against various targets, several reports showed that chronic stimulation of NK cells could increase LAG-3 surface expression and that of other coinhibitory receptors, which contributed to NK cell exhaustion and weakened the anti-tumor activity of NK cells In this situation, blocking LAG-3 could restore NK cells’ cytotoxic capacity [93, 94]. Ablation of CIS or blockade of the CIS-JAK pathway might unleash NK cell anti-tumor efficacy, and might become a novel therapeutic strategy for tumor immunotherapy, especially for the prevention of tumor metastasis
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