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.

Overcoming the Immunosuppressive Tumor Microenvironment in Multiple Myeloma

“…The therapeutic landscape for MM has been rapidly evolving due to introduction of targeted precision medicines, IMiDs, monoclonal antibodies, BiTEs, and CAR-T cells into multi-modality treatment strategies that have improved the survival outcomes [ 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 ].…”

Therapeutic Potential of Innate Lymphoid Cells for Multiple Myeloma Therapy

“…The trend is towards exhaustion with upregulation of expression of inhibitory ligands [ 151 , 152 ]. Among NKG2A, TIM-3, TIGIT, VISTA, KIRs, PD-1, CTLA4 and LAG-3, KIRs have been promising [ 153 , 154 , 155 ], but none have emerged as viable interventions in MM patients [ 156 ]. This may be due to the multiplicity of inhibitory pathways occurring and due to heterogeneity across, as well as temporally within, patients being trialled.…”

“…This may be due to the multiplicity of inhibitory pathways occurring and due to heterogeneity across, as well as temporally within, patients being trialled. Further research in this area, with a move towards personalisation, has been advocated [ 156 ].…”

Immunotherapy of Multiple Myeloma: Promise and Challenges

“…302 These include killer-cell immunoglobulin-like receptors (KIR), 259,303 CD47, 304,305 LAG3, 306 TIGIT, [307][308][309] and TIM-3. 310 In this connection, note should be made of an ongoing phase I/II trial (NCT04150965; N=104) in which RRMM patients receiving the anti-LAG3 relatlimab (BMS-986016) or anti-TIGIT BMS-986207 are compared to a control arm receiving a standard care regimen of elotuzumabpomalidomide-dexamethasone.…”