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, 3, e28497

Secretory Pathways Generating Immunosuppressive NKG2D Ligands: New Targets for Therapeutic Intervention


Secretory Pathways Generating Immunosuppressive NKG2D Ligands: New Targets for Therapeutic Intervention

Aroa Baragaño Raneros et al. Oncoimmunology.


Natural Killer Group 2 member D (NKG2D) activating receptor, present on the surface of various immune cells, plays an important role in activating the anticancer immune response by their interaction with stress-inducible NKG2D ligands (NKG2DL) on transformed cells. However, cancer cells have developed numerous mechanisms to evade the immune system via the downregulation of NKG2DL from the cell surface, including the release of NKG2DL from the cell surface in a soluble form. Here, we review the mechanisms involved in the production of soluble NKG2DL (sNKG2DL) and the potential therapeutic strategies aiming to block the release of these immunosuppressive ligands. Therapeutically enabling the NKG2D-NKG2DL interaction would promote immunorecognition of malignant cells, thus abrogating disease progression.

Keywords: NKG2D; NKs; exosomes; shedding; soluble NKG2D ligands.


Figure 1. Mechanisms involved in the release of soluble NKG2D and blocking strategies. Natural Killer Group 2 member D ligands (NKG2DL) may be released in a soluble form (sNKG2DL) to the extracellular environment mainly through proteolytic shedding mediated by metalloproteases, or by release in exosomes derived from the cell membrane. Blockage of these mechanisms facilitates the enhanced expression of NKG2DL on the surface of tumor cells promoting immune recognition. Several therapeutic strategies have been proposed to abrogate these NK2G2DL release mechanisms. These include: (A) Matrix metalloproteases (MMPs) inhibitors (MMPI II, MMPI III) can inhibit shedding of MHC class I related-A/B (MICA/B), while a disintigrin and metalloproteinases domains 10 and 17 (ADAM10 and 17) inhibitors (GW280264X, GI254023X) downregulate the release of sULBP2. The natural inhibitor of ADAM17 (TIMP3) blocks ADAM17 activity, preventing MICB shedding. (B) During hypoxia, nitric oxide levels are reduced, promoting the upregulation of hypoxia inducible factor 1, α subunit (HIF1α). Consequently, ADAM10 mRNA levels are upregulated, correspondingly enhancing the release of sMICA and sMICB. However, the restoration of nitric oxide levels by nitroglycerin (GTN) attenuates the shedding of these ligands. (C) Several chemotherapeutic drugs can regulate the production of sNKG2DL through the downregulation of mRNA expression of several metalloproteases (MMP2, MMP9, ADAM10, ADAM9). (D) Cytokines like interleukin-1β (IL-1β) or transforming growth factor β (TGFβ) reduce shedding of NKG2DL by transcriptional regulation of ADAM9 and NKG2DL. (E) Epigenetic drugs such as valproate (histone deacetilase inhibitor) and hydralazine (DNA methyltransferase inhibitor) may modulate the production of sNKG2DL by downregulating MMP9 or NKG2DL mRNA expression.

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