Platelet-mediated shedding of NKG2D ligands impairs NK cell immune-surveillance of tumor cells

Maurer, Stefanie; Kropp, Korbinian N.; Klein, Gerd; Steinle, Alexander; Haen, Sebastian P.; Walz, Juliane S.; Hinterleitner, Clemens; Märklin, Melanie; Kopp, Hans‐Georg; Salih, Helmut R.

doi:10.1080/2162402x.2017.1364827

Cited by 83 publications

(59 citation statements)

References 42 publications

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“…Shedding constitutes a very beneficial mean for cancer cells to avoid surface expression of these ligands. Metalloproteases, most prominently ADAM10, ADAM17 ( 40 , 41 ), and MMP14 ( 42 ) are frequently expressed in the tumor microenvironment but also on platelets ( 43 ), cleave and thereby remove MICA, MICB, or ULBP proteins from the tumor cell surface ( 44 – 48 ). The process of shedding is influenced by proteins that inhibit metalloprotease activity like TIMP3 ( 49 ), or that enable or facilitate the proteolytic cleavage, like the disulfide-isomerase ERp5 ( 50 ).…”

Section: Shedding-an Efficient Way To Evade From Nkg2d-mediated Survementioning

confidence: 99%

NKG2D Ligands–Critical Targets for Cancer Immune Escape and Therapy

2018

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DNA damage, oncogene activation and excessive proliferation, chromatin modulations or oxidative stress are all important hallmarks of cancer. Interestingly, all of these abnormalities also induce a cellular stress response. By upregulating “stress-induced ligands,” damaged or transformed cells can be recognized by immune cells and cleared. The human genome encodes eight functional “stress-induced ligands”: MICA, MICB, and ULBP1-6. All of them are recognized by a single receptor, NKG2D, which is expressed on natural killer (NK) cells, cytotoxic T cells and other T cell subsets. The NKG2D ligand/NKG2D-axis is well-recognized as an important mediator of anti-tumor activity; however, patient data about the role of NKG2D ligands in immune surveillance and escape appears conflicting. As these ligands are often actively transcribed, tumor cells are urged to manipulate the expression of these ligands on post-transcriptional or post-translational level. Although our knowledge on the regulation of NKG2D ligand expression remains fragmentary, research of the past years revealed multiple cellular mechanisms that are adopted by tumor cells to reduce the expression of “stress-induced ligands” and therefore escape immune recognition. Here, we review the post-transcriptional and post-translational mechanisms by which NKG2D ligands are modulated in cancer cells and their impact on patient prognosis.We discuss controversies and approaches to apply our understanding of the NKG2D ligand/NKG2D-axis for cancer therapy.

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Section: Shedding-an Efficient Way To Evade From Nkg2d-mediated Survementioning

confidence: 99%

NKG2D Ligands–Critical Targets for Cancer Immune Escape and Therapy

2018

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“…Shedding of NKG2DL by ADAM10 (and/or ADAM17) in turn impairs tumor-cell lysis by NK cells. We recently observed reduced surface expression of NKG2DL on tumor cells upon coculture with platelets or exposure to platelet releasate (120). This was mirrored by enhanced detection of soluble NKG2DL, pointing to increased shedding of the surface expressed ligands.…”

Section: Non-canonical Shedding Activity Of Padam10mentioning

confidence: 94%

Modulation of Immune Responses by Platelet-Derived ADAM10

et al. 2020

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Platelets have a crucial function in maintaining hemostasis. However, beyond their role in coagulation and thrombus formation, platelets have been implicated to affect various pathophysiological conditions such as infectious diseases, autoimmune disorders, and cancer. It is well-established that platelets aid local cancer growth by providing growth factors or contributing to cancer angiogenesis. In addition, they promote metastasis, among others by facilitation of tumor cell-extravasation and epithelial-to-mesenchymallike transition as well as protecting metastasizing cancer cells from immunosurveillance. A variety of membrane-bound and soluble platelet-derived factors are involved in these processes, and many aspects of platelet biology in both health and disease are regulated by platelet-associated metalloproteinases and their inhibitors. Platelets synthesize (i) members of the matrix metalloproteinase (MMP) family and also inhibitors of MMPs such as members of the "tissue inhibitor of metalloproteinases" (TIMP) family as well as (ii) members of the "a disintegrin and metalloproteinase" (ADAM) family including ADAM10. Notably, platelet-associated metalloproteinase activity not only influences functions of platelets themselves: platelets can also induce expression and/or release of metalloproteinases e.g., in leukocytes or cancer cells, and ADAMs are emerging as important components by which platelets directly affect other cell types and function. This review outlines the function of metalloproteinases in platelet biology with a focus on ADAM10 and discusses the role of platelet-derived metalloproteinases in the interaction of platelets with components of the immune system and/or cancer cells.

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“…Another intriguing ADAM10 dependent mechanism involved in the immune evasion of tumor cells from NK cell reactivity has been recently described. Of interest, ADAM10 was detected on platelet surface and contributed to NKG2D ligand cleavage from cancer cells (60). Moreover, ADAM10 has been found associated to exosome-like vesicles produced by Hodgkin lymphoma cells; thus, the activity of this protease might be spread in the tumor microenvironment, affecting the shedding process of NKG2D ligands and other substrates (61).…”

Section: Adam10 and Cancermentioning

confidence: 99%

NKG2D Ligand Shedding in Response to Stress: Role of ADAM10

et al. 2020

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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 proteasemediated 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.

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Platelet-mediated shedding of NKG2D ligands impairs NK cell immune-surveillance of tumor cells

Cited by 83 publications

References 42 publications

NKG2D Ligands–Critical Targets for Cancer Immune Escape and Therapy

NKG2D Ligands–Critical Targets for Cancer Immune Escape and Therapy

Modulation of Immune Responses by Platelet-Derived ADAM10

NKG2D Ligand Shedding in Response to Stress: Role of ADAM10

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