HLA class I, NKG2D, and natural cytotoxicity receptors regulate multiple myeloma cell recognition by natural killer cells

Abstract

IntroductionNatural killer (NK) cells are cytotoxic and cytokine-producing lymphocytes, involved in the immune defense against viral infections and tumors. 1 Their homeostasis is regulated by cytokines and membrane associate receptors able to inhibit or activate cellular programs. 2 The inhibitory receptors are well characterized and described extensively in several reviews. [3][4][5] Triggering of NK cells depends largely on NK receptor member D of the lectinlike receptor family (NKG2D) and natural cytotoxicity receptors (NCRs): NKp46, NKp44, NKp30. 6,7 NCRs are involved in the recognition of several tumor cell lines, although their ligands remain elusive. 6 NKG2D recognizes the MHC (major histocompatibility complex) class I chain-related (MIC) protein A (MICA) and B (MICB); both are nonclassic class I molecules. The UL16-binding proteins (ULBP1-3 or RAET1 proteins; ULBP1-3 in this paper) are the second group of NKG2D ligands in humans. MICs are expressed during virus infection or cell transformation; ULBP expression in fresh tumor cells is essentially unknown; only long-term cultured in vitro cell lines have been looked at so far. [8][9][10] Cytotoxic T lymphocytes (CTLs) and interferons (IFNs) have a key role in tumor progression and tumor "immune-editing process." 11 MHC class I molecule loss is a frequent event in tumor progression and could prevent CTL recognition. However, theoretically, NK cells could recognize MHC class I-defective tumors, according with the "missing self hypothesis." 12 So far, only in mouse models NK cells were demonstrated to destroy in vivo lymphoma and melanoma tumors with reduced MHC class I expression and/or with high levels of activating target structures. [13][14][15] Even though almost 30 years ago human NK cells were discovered for their in vitro antitumor cytotoxicity, we still have little information concerning the regulation of their antitumor activity in vivo or ex vivo. 16,17 Therefore, several questions remain to be addressed to understand the antineoplastic potential of human NK lymphocytes:1. HLA class I molecules are reported to be down-regulated during solid tumor progression. 18 19,20 Other hematopoietic-derived cells can stimulate NK lymphocytes as described for dendritic cells (DCs). 21 The B-cell membrane-associated proteins CD40 and CD1 regulate natural killer cell cytotoxicity. [22][23][24][25] Furthermore, NK lymphocytes are specifically activated after bone marrow graft but not by other tissue transplantations. 26 They localize in lymph nodes and spleen, mainly in B-cell follicles and in the marginal zone. 27 Blood, spleen, and bone marrow are the anatomic districts where the highest number and activity of NK cells are present. 1 Taking together these considerations, hematologic malignancies (B-cell-derived tumors in particular) could be considered an appealing system to investigate the potential role of NK cells in the control of tumor progression.Multiple myeloma (MM) is a plasma cell-derived tumor. It is characterized by accumulation of plasma cells in th...

Cellular immunotherapy in multiple myeloma: Lessons from preclinical models

“…In contrast, late-stage MM cells have a high MHC I and a low MICA expression, suggesting the emergence of NK-resistant subclones during disease progression [42]. These results are in accordance with reports describing an increase of NK-associated activation markers in early stage MM [43] and reduced NK-cell levels in untreated MM [18].…”

“…The production of TGF-β by myeloma and stromal cells contributes to the inhibitory effects on normal B-cell proliferation and antibody secretion [41]. [12,42].…”

Genotoxic Stress Induces Senescence-Associated ADAM10-Dependent Release of NKG2D MIC Ligands in Multiple Myeloma Cells

“…NKG2D was reported to play an important role in the NK cell-mediated killing of MM cells (17)(18)(19), and high levels of sMICA in sera of MM patients correlate with the disease stage, strongly suggesting sMICA as an independent prognostic factor in newly diagnosed MM patients (20,21).…”

The prognostic significance of soluble NKG2D ligands in B-cell chronic lymphocytic leukemia

“…4,5 NKG2DL, however, are stress-inducible and often found to be expressed on a variety of solid tumors and lymphoproliferative malignancies. [6][7][8][9][10][11][12][13][14][15] Consequently, the expression of both, the NKG2D receptor and its ligands, has a crucial role in immune defense mechanisms against tumor cells by T and NK cells: studies in mice showed that NK and CD8 T cells eliminated NKG2DL-positive tumor cells through the NKG2D receptor. 16,17 It was further shown that NKG2D protected the host from tumor initiation.…”