Targeting NK Cell Inhibitory Receptors for Precision Multiple Myeloma Immunotherapy.

Helmi Alfarra,Stacy Grieve,Jackson Weir,Tony Reiman

doi:10.3389/fimmu.2020.575609

Helmi Alfarra, Stacy Grieve + Show 2 more

Open Access

https://doi.org/10.3389/fimmu.2020.575609

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Abstract

Innate immune surveillance of cancer involves multiple types of immune cells including the innate lymphoid cells (ILCs). Natural killer (NK) cells are considered the most active ILC subset for tumor elimination because of their ability to target infected and malignant cells without prior sensitization. NK cells are equipped with an array of activating and inhibitory receptors (IRs); hence NK cell activity is controlled by balanced signals between the activating and IRs. Multiple myeloma (MM) is a hematological malignancy that is known for its altered immune landscape. Despite improvements in therapeutic options for MM, this disease remains incurable. An emerging trend to improve clinical outcomes in MM involves harnessing the inherent ability of NK cells to kill malignant cells by recruiting NK cells and enhancing their cytotoxicity toward the malignant MM cells. Following the clinical success of blocking T cell IRs in multiple cancers, targeting NK cell IRs is drawing increasing attention. Relevant NK cell IRs that are attractive candidates for checkpoint blockades include KIRs, NKG2A, LAG-3, TIGIT, PD-1, and TIM-3 receptors. Investigating these NK cell IRs as pathogenic agents and therapeutic targets could lead to promising applications in MM therapy. This review describes the critical role of enhancing NK cell activity in MM and discusses the potential of blocking NK cell IRs as a future MM therapy.

Highlights

Multiple myeloma (MM) is characterized by the accumulation of malignant plasma cells (PCs), resulting in increased monoclonal protein in the blood and urine [1]
MM is a progressive disease that begins as an asymptomatic precursor called monoclonal gammopathy of undetermined significance (MGUS), before developing into smoldering MM (SMM), and fully active symptomatic MM
In in-vivo established MM xenografts, Natural killer (NK) cells recruitment to tumor sites was not associated with lenalidomide, this recruitment could be enhanced by the addition of elotuzumab, likely through an antibody dependent cellular cytotoxicity (ADCC)-mediated mechanism [108]. Another in-vitro study on bone marrow (BM) mononuclear cells from MM patients have been shown that combination of daratumumab-IPH2102 anti-killer cell immunoglobulin-like receptors with lenalidomide have improved the NK cell ADCC activity and myeloma cell lysis [108, 109] (Figure 3B)

Summary

Introduction

Multiple myeloma (MM) is characterized by the accumulation of malignant plasma cells (PCs), resulting in increased monoclonal protein in the blood and urine [1]. Myeloma cells harvested from MM patients from the BM early in disease progression expressed a relatively low level of HLA Class I ligands and were subsequently responsive to the NK cell mediated cytotoxicity.

Results

Conclusion