Abstract
There is compelling clinical and experimental evidence to suggest that natural killer (NK) cells play a critical role in the recognition and eradication of tumors. Efforts at using NK cells as antitumor agents began over two decades ago, but recent advances in elucidating NK cell biology have accelerated the development of NK cell-targeting therapeutics. NK cell activation and the triggering of effector functions is governed by a complex set of activating and inhibitory receptors. In the early phases of cancer immune surveillance, NK cells directly identify and lyse cancer cells. Nascent transformed cells elicit NK cell activation and are eliminated. However, as tumors progress, cancerous cells develop immunosuppressive mechanisms that circumvent NK cell-mediated killing, allowing for tumor escape and proliferation. Therapeutic intervention aims to reverse tumor-induced NK cell suppression and sustain NK cells’ tumorlytic capacities. Here, we review tumor–NK cell interactions, discuss the mechanisms by which NK cells generate an antitumor immune response, and discuss NK cell-based therapeutic strategies targeting activating, inhibitory, and co-stimulatory receptors.
Highlights
The recent FDA approvals of the programmed cell death protein 1 (PD-1)-targeted checkpoint inhibitors pembrolizumab and nivolumab mark the latest successes in the rapidly expanding field of cancer immunotherapies
We have demonstrated that this killer cell immunoglobulin-like receptor (KIR)-mediated antibody-dependent cell-mediated cytotoxicity (ADCC) suppression can be overcome by combining rituximab with anti-KIR monoclonal antibody (mAb) therapy [84]
natural killer (NK) cells have novel mechanisms of participating in immune defense, making them uniquely appealing for cancer immunotherapy
Summary
The recent FDA approvals of the programmed cell death protein 1 (PD-1)-targeted checkpoint inhibitors pembrolizumab and nivolumab mark the latest successes in the rapidly expanding field of cancer immunotherapies. Immunotherapy represents a paradigm shift in cancer treatment; instead of targeting tumor cells, the goal of immunotherapy is to augment and expand the immune system’s intrinsic antitumor response. Diverse immunotherapeutic modalities have been accepted as viable strategies for eliminating cancerous cells. Cancer vaccines, adoptive cell transfers, and especially checkpoint inhibitors constitute valuable elements in the immunotherapeutic armamentarium. A class of important immune-modulators is conspicuously absent: agents that utilize the power of innate immune cells to eradicate tumors. An important class of innate immune cells that play a critical role in mediating the antitumor immune response is the natural killer (NK) cell
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