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

• Main Authors: Jacob J. Orme, Khalid A. Jazieh, Tiancheng Xie, Susan Harrington, Xin Liu, Matthew Ball, Benjamin Madden, M. Cristine Charlesworth, Tariq U. Azam, Fabrice Lucien, Bharath Wootla, Yanli Li, Jose Caetano Villasboas, Aaron S. Mansfield, Roxana S. Dronca, Haidong Dong
• Format: Article
• Language: English
• Published: Taylor & Francis Group 2020-01-01
• Series: OncoImmunology
• Subjects: pd-1 resistance; checkpoint inhibitor resistance; spd-l1; adam10; adam17
• Online Access: http://dx.doi.org/10.1080/2162402X.2020.1744980

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.