Targeting NK Cell Checkpoint Receptors or Molecules for Cancer Immunotherapy

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.

Arrested development: suppression of NK cell function in the tumor microenvironment

“…These initial breakthroughs have focused on ICB, an antibody (Ab)‐mediated therapy where blocking Abs are used to inhibit regulatory surface proteins such PD‐1, programmed death‐ligand 1 (PD‐L1) and cytotoxic T lymphocyte‐associated antigen 4 (CTLA‐4), which suppress T‐cell activation 101 . In addition to these three targets, a number of new surface receptors such as T‐cell immunoglobulin and mucin‐domain‐containing molecule 3 (TIM‐3), T‐cell immunoreceptor with Ig and immunoreceptor tyrosine‐based inhibition motif domains (TIGIT), LAG‐3 and CD96 have been found on multiple immune cell types such T cells, NK cells and dendritic cells and are being recognised for their potential as additional ICB targets 102–104 and has been reviewed previously 105 . These inhibitory pathways are fairly well understood in T cells but further understanding of the underlying biological mechanisms across the immune landscape in the TME will be useful in designing new ICB therapies.…”

The Immune Checkpoint PD-1 in Natural Killer Cells: Expression, Function and Targeting in Tumour Immunotherapy

“…mAbs are widely used to treat different tumour types and have been shown to improve NK-dependent anti-tumour immune activity [48,62,143]. Recently, it has been proposed that sPD-1 might instead be more effective than mAbs in restoring the immune response.…”

Natural Killer Cells in Immunotherapy: Are We Nearly There?

“…NK cells express a wide variety of inhibitory receptors, including NKG2A, KIRs (such as KIR3DL2), PD-1, TIGIT, TIM-3, and LAG-3. Monoclonal antibodies that block inhibitory receptors have shown great efficacy in enhancing T cell/CAR-T cell anti-tumor activity, and a number of clinical trials are currently ongoing that are testing some of these checkpoint blockade molecules as a means to enhance endogenous T cell and NK cell activity (reviewed in [34]).…”