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. 2020 Mar 25;11:447. doi: 10.3389/fimmu.2020.00447

FIGURE 1.

FIGURE 1

Genotoxic stress promotes ADAM10-mediated shedding of MIC molecules in multiple myeloma. (A) Genotoxic stress induced by chemotherapeutic drugs increases cell-surface expression of NKG2D ligands and ADAM10 expression levels and activity through the induction of ROS-dependent DNA damage response. Both NKG2D ligand and ADAM10 upregulation are mainly associated with a senescent phenotype. An increase of the ADAM10-mediated shedding process is observed only for MIC molecules sensitive to protease cleavage (i.e., MICA*019 or MICB), whereas MICA*008 release is not perturbed. (B) Genotoxic stress-induced MICA/B shedding favors the accumulation of soluble ligands in the tumor microenvironment that can contribute to the desensitizing of NK cells. (C) The combined use of chemotherapeutic agents and ADAM10 inhibitors determines a stabilization of NKG2D ligands on MM cell surface, promoting NK cell-mediated immune surveillance. MM, multiple myeloma; ROS, reactive oxygen species; GPI, glycosylphosphatidylinositol; SASP, senescent-associated secretory phenotype.