NK cells and multiple myeloma-associated endothelial cells: molecular interactions and influence of IL-27

Area of Science:

• Immunology
• Oncology
• Cell Biology

Background:

• Multiple Myeloma (MM) is an incurable malignancy characterized by tumor angiogenesis.
• Tumor-associated endothelial cells in MM bone marrow play a role in disease progression.

Purpose of the Study:

• To investigate the anti-tumor activity of cytokine-stimulated Natural Killer (NK) cells against Multiple Myeloma endothelial cells (MMECs).
• To evaluate the role of IL-15 and IL-27 in modulating NK cell function and their interaction with MMECs.

Main Methods:

• Isolation of MMECs from bone marrow aspirates of MM patients.
• Activation of NK cells with Interleukin-15 (IL-15) and Interleukin-27 (IL-27).
• Assessment of NK cell-mediated cytotoxicity, cytokine production (IFN-γ), and surface receptor expression (NKp46, PD-L1, PD-L2, HLA-I, HLA-II).

Main Results:

• NK cells activated with IL-15 demonstrated cytotoxicity against MMECs, involving DNAM-1 recognition due to high PVR and Nectin-2 expression on MMECs.
• PVR surface density was significantly higher on MMECs from active MM patients compared to those in remission or MGUS.
• IL-27 maintained or enhanced IL-15-induced NK cell functions, including MMEC killing, IFN-γ production, and increased NKp46 expression.
• IL-27 upregulated PD-L2 and HLA-I expression on tumor endothelium without affecting PD-L1 and HLA-II.

Conclusions:

• Cytokine-activated NK cells, particularly when modulated by IL-27, exhibit potent anti-MMEC activity.
• IL-27 enhances NK cell effector functions and modulates tumor endothelium, suggesting a potential therapeutic role.
• NK cell-based immunotherapies, potentially combined with IL-27, could improve outcomes for Multiple Myeloma patients.