A secreted PD-L1 splice variant that covalently dimerizes and mediates immunosuppression

Mahoney, Kathleen M.; Shukla, Sachet A.; Patsoukis, Nikolaos; Chaudhri, Apoorvi; Browne, Edward P.; Arazi, Arnon; Eisenhaure, Thomas; Pendergraft, William F.; Hua, Peng; Pham, Hung C.; Bu, Xia; Zhu, Baogong; Hacohen, Nir; Fritsch, Edward F.; Boussiotis, Vassiliki A.; Wu, Catherine J.; Freeman, Gordon J.

doi:10.1007/s00262-018-2282-1

Cited by 108 publications

(113 citation statements)

References 35 publications

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“…published secreted PD-L1 splice variants. 22 While we observed that PD-L1 is also shed from the surface of extracellular vesicles, further work is required to determine the relative contribution of exosome-derived sPD-L1 to resistance. It is also uncertain whether removal of either ADAM10 or ADAM17 alone, as in our siRNA studies but not in our peptide and antibody inhibitor experiments, is sufficient to rescue PD-(L)1 inhibitor sensitivity.…”

Section: Discussionmentioning

confidence: 78%

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ADAM10 and ADAM17 cleave PD-L1 to mediate PD-(L)1 inhibitor resistance

et al. 2020

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2020) ADAM10 and ADAM17 cleave PD-L1 to mediate PD-(L)1 inhibitor resistance, ABSTRACT ADAM10 and ADAM17 expression and soluble PD-L1 (sPD-L1) predict poor prognosis in many malignancies, including in patients treated with PD-(L)1 inhibitors. The mechanism of soluble PD-L1 production and its effects are unknown. Here we uncover a novel mechanism of ADAM10-and ADAM17-mediated resistance to PD-(L)1 inhibitors. ADAM10 and ADAM17 cleave PD-L1 from the surface of malignant cells and extracellular vesicles. This cleavage produces an active sPD-L1 fragment that induces apoptosis in CD8 + T cells and compromises the killing of tumor cells by CD8 + T cells. Reduced tumor site PD-L1 protein-to-mRNA ratios predict poor outcomes and are correlated with elevated ADAM10 and ADAM17 expression in multiple cancers. These results may explain the discordance between PD-L1 immunohistochemistry and PD-(L)1 inhibitor response. Thus, including ADAM10 and ADAM17 tissue staining may improve therapy selection. Furthermore, treatment with an ADAM10/ADAM17 inhibitor may abrogate PD-(L)1 inhibitor resistance and improve clinical responses to PD-(L)1 immunotherapy. ARTICLE HISTORY Materials and methods Cell cultureMalignant cell lines 786-0, Karpas-299, and Du145 (ATCC) were grown in RPMI 1640 (Invitrogen) supplemented by 10%

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Section: Discussionmentioning

confidence: 78%

“…The source of soluble PD-L1 is uncertain. While others have reported secreted PD-L1 splice variants, 22 we hypothesized that PD-L1 may be cleaved from the surface of tumor cells. In particular, closely related metzincin metalloproteinases ADAM10 and ADAM17 commonly cleave immune cell surface ligands.…”

Section: Resultsmentioning

confidence: 96%

ADAM10 and ADAM17 cleave PD-L1 to mediate PD-(L)1 inhibitor resistance

et al. 2020

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“…An in vitro experiment demonstrated that a splice variant form of PD-L1 (secPD-L1) could inhibit T-cell proliferation. secPD-L1 has been detected in malignant cells but can also be considered a negative immune regulator in pregnancy complications (61). Taken together, these results suggest that the PD-1/B7-H1 checkpoint maintains the local immunological environment by interacting with different immune cells and mediating cytokine secretion.…”

Section: B7-h1 and B7-dcmentioning

confidence: 83%

The Role of B7 Family Molecules in Maternal–Fetal Immunity

2020

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Pregnancy is a complex but well-arranged process, and a healthy fetus requires immune privilege and surveillance in the presence of paternally derived antigens. Maternal and fetal cells interact at the maternal-fetal interface. The upregulation and downregulation of maternal immunity executed by the leukocyte population predominantly depend on the activity of decidual natural killer cells and trophoblasts and are further modulated by a series of duplex signals. The B7 family, which consists of B7-1, B7-2, B7-H1, B7-DC, B7-H2, B7-H3, B7-H4, B7-H5, BTNL2, B7-H6, and B7-H7, is one of the most characterized and widely distributed signaling molecule superfamilies and conducts both stimulatory and inhibitory signals through separate interactions. In particular, the roles of B7-1, B7-2, B7-H1, and their corresponding receptors in the progression of normal pregnancy and some pregnancy complications have been extensively studied. Together with the TCR-MHC complex, B7 and its receptors play a critical role in cell proliferation and cytokine secretion. Depending on this ligand-receptor crosstalk, the balance between the tolerance and rejection of the fetus is perfectly maintained. This review aims to provide an overview of the current knowledge of the B7 family and its functions in regulating maternal-fetal immunity through individual interactions.

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“…Further interest attracts the measurement of PD-L1 (soluble and expressed in extracellular vesicles, EV) in liquid biopsies. Soluble PD-L1 is a splice variant without a transmembrane domain capable to directly inhibit T cell proliferation and IFN-γ production [94]. Elevated basal levels of soluble PD-L1 in the plasma of melanoma patients was associated with progressive disease [95].…”

Section: Predicting the Response To The Ici Therapymentioning

confidence: 99%

Modern Aspects of Immunotherapy with Checkpoint Inhibitors in Melanoma

Petrova

Arkhypov

Weber

et al. 2020

IJMS

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Although melanoma is one of the most immunogenic tumors, it has an ability to evade anti-tumor immune responses by exploiting tolerance mechanisms, including negative immune checkpoint molecules. The most extensively studied checkpoints represent cytotoxic T lymphocyte-associated protein-4 (CTLA-4) and programmed cell death protein 1 (PD-1). Immune checkpoint inhibitors (ICI), which were broadly applied for melanoma treatment in the past decade, can unleash anti-tumor immune responses and result in melanoma regression. Patients responding to the ICI treatment showed long-lasting remission or disease control status. However, a large group of patients failed to respond to this therapy, indicating the development of resistance mechanisms. Among them are intrinsic tumor properties, the dysfunction of effector cells, and the generation of immunosuppressive tumor microenvironment (TME). This review discusses achievements of ICI treatment in melanoma, reasons for its failure, and promising approaches for overcoming the resistance. These methods include combinations of different ICI with each other, strategies for neutralizing the immunosuppressive TME and combining ICI with other anti-cancer therapies such as radiation, oncolytic viral, or targeted therapy. New therapeutic approaches targeting other immune checkpoint molecules are also discussed.

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A secreted PD-L1 splice variant that covalently dimerizes and mediates immunosuppression

Cited by 108 publications

References 35 publications

ADAM10 and ADAM17 cleave PD-L1 to mediate PD-(L)1 inhibitor resistance

ADAM10 and ADAM17 cleave PD-L1 to mediate PD-(L)1 inhibitor resistance

The Role of B7 Family Molecules in Maternal–Fetal Immunity

Modern Aspects of Immunotherapy with Checkpoint Inhibitors in Melanoma

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