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Review
. 2020 Mar 21;9(3):768.
doi: 10.3390/cells9030768.

NK cells and CD38: Implication for (Immuno)Therapy in Plasma Cell Dyscrasias

Renato Zambello  1   2 , Gregorio Barilà  1   2 , Sabrina Manni  1   2 , Francesco Piazza  1   2 , Gianpietro Semenzato  1   2
Affiliations
Review

NK cells and CD38: Implication for (Immuno)Therapy in Plasma Cell Dyscrasias

Renato Zambello et al. Cells. .

Abstract

Immunotherapy represents a promising new avenue for the treatment of multiple myeloma (MM) patients, particularly with the availability of Monoclonal Antibodies (mAbs) as anti-CD38 Daratumumab and Isatuximab and anti-SLAM-F7 Elotuzumab. Although a clear NK activation has been demonstrated for Elotuzumab, the effect of anti-CD38 mAbs on NK system is controversial. As a matter of fact, an initial reduction of NK cells number characterizes Daratumumab therapy, limiting the potential role of this subset on myeloma immunotherapy. In this paper we discuss the role of NK cells along with anti-CD38 therapy and their implication in plasma cell dyscrasias, showing that mechanisms triggered by anti-CD38 mAbs ultimately lead to the activation of the immune system against myeloma cell growth.

Keywords: CD38; NK cells; multiple myeloma.

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Conflict of interest statement

The Authors report no conflicts of interest related to this work.

Figures

Figure 1
Figure 1
Mechanisms accounting for cytotoxic activity of NK cells. (A) FCγRIII/CD16-expressing NK cells release cytotoxic molecules such as perforin and granzymes contained in NK cell granules, which enter in the target cell/tumor cell leading to its apoptosis through caspase-1,3,7 activation, cytochrome C release and IL-1β expression. (B) TNFR family ligands (TNF, FasL or TRAIL) are expressed on, or secreted by NK cells and by binding to their receptors (TNFR1, Fas or TRAIL-R) on the target/tumor cell, induce its apoptosis through Caspase 8 activation. (C) The binding of FCγRIII/CD16 to an antibody (Ab) recognizing a target antigen on the tumor cell, induces its apopotosis through ADCC. Abbreviations used: NK= Natural Killer; ADCC (antibody dependent cell cytotoxicity); TNF= tumor necrosis factor; TNFR= tumor necrosis factor receptor; FasL= Fas ligand; TRAIL= TNF-related apoptosis-inducing ligand; TRAIL-R= TNF-related apoptosis-inducing ligand-receptor; Ab= antibody; IL-1β= Interleukin 1β.
Figure 2
Figure 2
CD38 expression and function in NK cells. (A) Role of CD38 in the activation of NK cells. (B) Role of CD38 in the functional activity of CD56bright/CD16- NK cells.
Figure 3
Figure 3
Effects of anti-CD38 therapy on immune cell levels in MM. Anti-CD38 monoclonal antibodies (anti-CD38 mAb) have shown a cytotoxic effect on MM plasma cells (PC) even in the presence of protective bone marrow stromal cells, through CDC (complement-dependent cytotoxicity), ADCC (antibody-dependent cellular cytotoxicity), ADCP (antibody-dependent cellular phagocytosis), and apoptosis after cross-linking. Anti-CD38 mAb increased the frequency, clonality and function of T-helper (Th) and T-cytotoxic (TC) cells, and CD38low NK cells, while depleting CD38high NK and CD38-expressing T-reg (TR) suppressor cells.
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