Abstract

NKG2D is an activating receptor expressed by NK cells and some subsets of T cells and represents a major recognition receptor for detection and elimination of cancer cells. The ligands of NKG2D are stress-induced self-proteins that can be secreted as soluble molecules by protease-mediated cleavage. The release of NKG2D ligands in the extracellular milieu is considered a mode of finely controlling their surface expression levels and represents a relevant immune evasion mechanism employed by cancer cells to elude NKG2D-mediated immune surveillance. A disintegrin and metalloproteinase 10 (ADAM10), a catalytically active member of the ADAM family of proteases, is involved in the cleavage of some NKG2D ligands in various types of cancer cells either in steady state conditions and in response to an ample variety of stress stimuli. Appealing immunotherapeutic strategies devoted to promoting NK cell-mediated recognition and elimination of cancer cells are based on the upregulation of NK cell activating ligands. In particular, activation of DNA damage response (DDR) and the induction of cellular senescence by chemotherapeutic agents are associated with increased expression of NKG2D ligands on cancer cell surface. Herein, we will review advances on the protease-mediated cleavage of NKG2D ligands in response to chemotherapy-induced stress focusing on: (i) the role played by ADAM10 in this process and (ii) the implications of NKG2D ligand shedding in the course of cancer therapy and in senescent cells.

Highlights

  • Natural killer cells are innate lymphocytes implicated in the immune surveillance of cancer cells by the integration of signals deriving from numerous cell-surface activating and inhibitory receptors [1]

  • We will discuss about the protease-mediated cleavage of NKG2D ligands on cancer cells in response to stress stimuli focusing our attention on: (i) the role played by A disintegrin and metalloproteinase 10 (ADAM10) in this process; (ii) the mechanisms regulating ADAM10 expression and activity in cancer cells; (iii) the implications of NKG2D ligand shedding in the course of cancer therapy

  • Mechanisms regulating the shedding of NKG2D ligands in response to stress stimuli are not completely known, and different metalloproteases could be involved in such process, we will focus our attention on a number of studies showing modulation of NKG2D ligand shedding related to a concomitant change of ADAM10 expression/activity

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Summary

Introduction

Natural killer cells are innate lymphocytes implicated in the immune surveillance of cancer cells by the integration of signals deriving from numerous cell-surface activating and inhibitory receptors [1]. Activation of DNA damage response (DDR) and the induction of cellular senescence by chemotherapeutic agents are associated with increased expression of NKG2D ligands on cancer cell surface [31, 32].

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