Altered expression of the ADAM (A Disintegrin and Metalloproteinase) proteins, usually
involved in biological processes such as proteolysis, cell adhesion, proliferation,
migration, and signaling, has been associated with several diseases including asthma,
arthritis, neurodegenerative diseases, atherosclerosis, and cancer (1–4). Also, ADAM10
is involved in the pathogenesis of autoimmune diseases such as multiple sclerosis
or systemic lupus erythematosus, and the development of inflammation or allergy (5,
6). This Special Issue is focused on the pathophysiological role of ADAM10 in tumors
and autoimmunity, including potential therapeutic targeting of this enzyme with specific
The best-characterized function of ADAM10 is the proteolytic cleavage of different
transmembrane proteins, a process known as “ectodomain shedding” that targets the
extracellular domain of several types of cell surface molecules (1, 2). Other functions
of this enzyme are not directly related to the activation of its catalytic domain
but rather due to its exosite, that is a secondary substrate-binding site (7).
In particular, ADAM10 has been reported to shed the “stress-induced” molecules MICA,
MICB, and ULBPs expressed on the cancer cell surface (8–11). These molecules are responsible
for inducing an immune response against cancer cells upon binding to NKG2D receptors
that are expressed on natural killer (NK) cells and most cytotoxic T lymphocytes.
The ADAM10-mediated proteolytic shedding of these NKG2D ligands (NKG2DL) into the
extracellular milieu can impair the recognition of cancer cells by T or NK cells (9–11).
This mechanism has been evidenced in many types of tumors including melanoma, various
carcinomas, and hematopoietic malignancies such as chronic lymphocytic leukemia, acute
myeloid leukemia, non-Hodgkin and Hodgkin's lymphomas (12, 13). In the latter neoplasia,
ADAM10-mediated CD30 shedding is reported to impair the recognition of this molecule
by therapeutic monoclonal antibodies, in addition to the reduced immune surveillance
through enhanced NKG2DL shedding (12–14).
The contribution by Zingoni et al. provides a topical overview of the tumor-associated
up-regulation of NKG2DL and the cell stress-regulated ADAM10 activity mediating NKG2DL
shedding in the context of carcinogenesis and cancer therapy. They highlight enhanced
NKG2DL shedding in response to chemotherapy-induced cellular senescence of tumor cells
as a consequence of both, induced NKG2DL expression and ADAM10 activity. Similarly,
therapeutic targeting of the DNA damage response (DDR) affects the release of soluble
NKG2DL by tumor cells through induction of NKG2DL and modulating ADAM10 expression
and activity. They emphasize that targeting ADAM-mediated shedding of NKG2DL in the
course of cancer therapies may restore immune detection and elimination of tumor cells
via the NKG2D axis.
Hansen et al. explain how CD30 processing, due to the activity of ADAM10, might influence
the impact of CD30 antibody-drug conjugates, such as Brentuximab Vedotin, reducing
their efficacy in Hodgkin lymphomas, as previously described by the same group. This
review evidences that the enzyme is catalytically active in extracellular vesicles
and gradually releases sCD30, that can be measured in the patients' plasma, creating
a “crossfire effect” that may modulate the response to therapy (16).
In turn, Maurer et al. point out a peculiar function of platelet-associated ADAM10.
ADAM10 is highly expressed by platelets, where it is not only of major relevance in
regulating hemostasis but also appears to contribute to the metastasis-promoting effect
of platelets. This review comprehensively lists ADAM10 target structures of platelets
and discusses various modes of ADAM10-mediated shedding including canonical shedding
(in cis) and non-canonical shedding (in trans). Further, the authors summarize new
insights into the world of proteins involved in ADAM10 processing, trafficking, and
modulation such as TspanC8 tetraspanins, as reported by others (15), and TIMPs. Overall,
this review illustrates the multifaceted role of ADAM10 expressed by platelets.
For all these reasons, in the last decade, an increasing interest has emerged toward
the development of selective ADAMs ligands for their potential use for early-stage
diagnosis and therapy of cancer (16–19). Several ADAM10 inhibitors proved to be effective
in reducing tumor cell growth, inducing anti-tumor immune reactions or enhancing the
effect of therapeutic antibody-drug conjugates in vitro. Examples are given by studies
in gliomas, solid cancers, and hematologic tumors, including Hodgkin lymphoma (14,
Some recent ADAM10 blockers proved to rescue both anti-tumor effect of Brentuximab
Vedotin and sensitivity of Reed-Sternberg cells to effector lymphocytes, in particular
through the antibody-dependent cellular cytotoxicity elicited by the therapeutic monoclonal
antibody Iratumumab (20–24). Interestingly, these inhibitors were also carried by
exosomes, making them able to spread their effects into the microenvironment (24).
This points to the importance of targeting ADAM10 on different cell types, since exosomes
can be released, for instance, by mesenchymal stromal cells or fibroblasts or accessory
cells at the site of the lesion (24, 25). Very recently, cleavage of PD-L1 from lymphoma
and solid tumor cells by ADAM10 and ADAM17 has been reported (26, 27). The consequent
release of soluble PD-L1 was shown to induce apoptosis of immunocompetent CD8 T cells
leading to an impairment of the anti-tumor immune response (27). This mechanism may
confer resistance to PD-(L)1 blockers, thereby playing a role in tumor-mediated immunosuppression.
Hence, it is conceivable to consider ADAM10/17 inhibitors also for an improvement
of immunotherapies targeting the PD-1/PD-L1 axis.
However, despite the considerable number of studies generating significant data, the
clinical trials have not confirmed the initial encouraging results and effective compounds
are still missing.
The contributions by Smith et al. and by Minond et al. face this problem from two
different viewpoints. The former reports on recent pre-clinical data with inhibitors
and clinical data supporting the use of ADAM10 inhibitors in cancer and autoimmunity,
searching for a mean to improve the potency and efficiency of anti-ADAM10 products
alone or paired with other drug treatments (Smith et al.). The latter introduces the
importance of ADAM10 non-catalytic domain, called exosite, addressing the possibility
to target the exosite and, in particular, the glycosylation sites of ADAM10 (Minond).
This suggests that proteolysis of specific ADAM10 substrates involved in various diseases
can be targeted using knowledge on their glycosylation as well as on differences in
their non-catalytic domains (28, 29). These results may open new avenues to circumvent
the poor selectivity of inhibitors for ADAM10 and/or for ADAM10 substrates that currently
represents the main obstacle to develop efficient drugs. Such novel targeting concepts
introduce a new perspective for therapeutic approaches involving ADAM10 inhibitors
in a wide spectrum of diseases.
MZ, AR, AP, and AS planned, wrote, and revised the editorial manuscript. All authors
contributed to the article and approved the submitted version.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial
or financial relationships that could be construed as a potential conflict of interest.