Modulation of Immune Responses by Platelet-Derived ADAM10

Abstract

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.

Platelet-expressed immune checkpoint regulator GITRL in breast cancer

“…Implementing further information on the phenotypic imprint of platelet-expressed immune checkpoint molecules [ 8 ] which is part of ongoing studies will certainly further support our understanding of platelets as valuable diagnostic tools. Platelets have already been suggested as biomarkers as they are readily available for liquid biopsies [ 40 , 41 ]. Especially in breast cancer, as shown in our study, pGITRL might be useful as a marker of metastasis.…”

Associations of Platelet Count with Inflammation and Response to Anti-TNF-α Therapy in Patients with Ankylosing Spondylitis

“…Despite the roles of platelets in hemostasis and thrombosis, their roles in regulating inflammation and immunity have gained increasing attentions in recent years ( Maurer et al, 2020 ; Rayes et al, 2020 ; van der Poll and Parker, 2020 ). Platelets have been recognized as crucial regulators of inflammatory processes under various pathophysiological conditions ( Karhausen et al, 2020 ).…”

Platelet-Expressed TNFRSF13B (TACI) Predicts Breast Cancer Progression

“…TACI has been found to be proteolytically shed from the surface of activated B cells by the matrix metalloproteinase “a disintegrin and metalloproteinase” 10 (ADAM10) ( 27 ). Since ADAM10 is expressed by platelets ( 28 , 29 ), we set out to assess whether the latter is involved in regulating pTACI surface level. Basal expression of pTACI on resting platelets was not altered in the presence of the broad spectrum matrix metalloproteinase inhibitor Batimastat or the ADAM10 inhibitor GI254023 ( Figure 3F , left panel).…”

“…Together, these data indicate that proteolytic cleavage of pTACI is at least in part responsible for pTACI downregulation in activated platelets. Platelets express ADAM10 which may modulate several pathways in the TME ( 29 ). The question whether ADAM10 - and in particular platelet-derived ADAM10 - is relevant for pTACI shedding in vivo needs to be further investigated.…”