Targeting NK Cell Inhibitory Receptors for Precision Multiple Myeloma Immunotherapy

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.

Keywords: chimeric antigen receptor NK; immune checkpoint inhibitor; immunotherapy; inhibitory receptors of lymphocytes; monoclonal antibody therapy; multiple myeloma; natural killer cell; precision medicine.

Figure 1

Restoring NK Cells by Targeting Their IRs. (A) Left: inactive NK cell has inhibitory receptors and complimentary ligands on the myeloma cell. (B) Right: NK cell activated when inhibitory axis is blocked via specific blocking mAbs. Figure created with BioRender.com.

Figure 2

NK cell Surveillance of Cancer Cell (A) The presence of inhibitory signals and lack of activating signals prevents the activation of the NK cells which avoids the lysis of the healthy cells. (B) NK cell recognizes the cancer cell due to the lack of human leukocyte antigens (HLAs) and/or other inhibitory ligands on cancer cell (“missing-self hypothesis”), which results in production of cytokines, granzyme B and perforins that leads to the cancer cell killing. This scenario is simplified. Activation signals are still necessary to induce activation as the absence of inhibitory signals alone is usually insufficient. (C) NK cell is activated via the activating signals and the engagement with the activating ligands on the cancer cell in the lack of inhibitory signals, which leads to the production of perforins and granzyme B and cytokines, which ultimately yields cancer cell killing. Figure created with BioRender.com.

Figure 3

NK Cell Restoration Approaches for Multiple Myeloma Immunotherapy. (A) NK cell impairment in MM is characterized by (1) immunosuppressive cells and cytokines (2) low NK cell numbers (3) inhibitory and activating receptor imbalance in favor of NK cell inhibition (4) downregulation of activating ligands on cancer cell. Multiple myeloma cells in an impaired NK cell environment evade detection and continue proliferation. (B) Several therapeutic interventions can overcome NK cell impairment. Checkpoint inhibitors block inhibitory receptors to unleash NK cell cytotoxicity. Antibody-dependent cellular cytotoxicity (ADCC) uses mAbs designed to bind tumor-specific antigens and mediate anti-myeloma NK cell killing. Immunomodulatory drugs (IMiDs), proteosome inhibitors (PIs), histone deacetylase inhibitors (HADCi) and cytokines can upregulate activating ligands (ALs) and downregulate inhibitory ligands (ILs) on cancerous cells, upregulate activating receptors (ARs) and IFN-γ in NK cells, as well as promote NK cell proliferation. CAR-NK cells are engineered to target tumor-specific antigens and kill cancerous cells upon introduction to patient. TGFβ is Transforming growth factor beta, PGE2 is Prostaglandin E. Figure created with BioRender.com.