@article{aa8621a3574e48c69f286274109513eb,
title = "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.",
keywords = "ADAM10, ADAM17, PD-1 resistance, checkpoint inhibitor resistance, sPD-L1",
author = "Orme, {Jacob J.} and Jazieh, {Khalid A.} and Tiancheng Xie and Susan Harrington and Xin Liu and Matthew Ball and Benjamin Madden and Charlesworth, {M. Cristine} and Azam, {Tariq U.} and Fabrice Lucien and Bharath Wootla and Yanli Li and Villasboas, {Jose Caetano} and Mansfield, {Aaron S.} and Dronca, {Roxana S.} and Haidong Dong",
note = "Funding Information: R21 5R21CA197878-02 Role of Bim and soluble B7-H1 in monitoring T cell responses to anti-PD-1 therapy in melanoma (HD and RD) L30 CA231541-01 Soluble B7H1 as a PD1 Checkpoint “Remote Control” in Cancer (JJO) Richard M. Schulze Family Foundation (HD and RD). Statistical guidance was provided generously by Nathan Foster and Paul Novotny of the Mayo Clinic Center for Clinical and Translational Science (CCaTS). Technical guidance for working with TCGA data was provided generously by Jeran Stratford. The authors acknowledge the help of Jacob Hirdler in performing an experiment. Some illustrations were created using Servier Medical Art templates, which are licensed under a Creative Commons Attribution 3.0 Unported License; https://smart.servier.com. The results shown here are in part based upon data generated by the TCGA Research Network: https://www.cancer.gov/tcga. Publisher Copyright: {\textcopyright} 2020, {\textcopyright} 2020 The Author(s). Published with license by Taylor & Francis Group, LLC.",
year = "2020",
month = jan,
day = "1",
doi = "10.1080/2162402X.2020.1744980",
language = "English (US)",
volume = "9",
journal = "OncoImmunology",
issn = "2162-4011",
publisher = "Landes Bioscience",
number = "1",
}