Elucidating the mechanism of ADAM10/PD-L1 interaction in pancreatic adenocarcinoma cell lines using cellular and computational analyses.

Abstract

Targeting the immune checkpoint programmed cell death-ligand 1 (PD-L1) faces diverse challenges against pancreatic ductal adenocarcinoma (PDAC), the most common type of cancer-related death. Shedding of PD-L1 from the tumor cell surface by A Disintegrin And Metalloprotease 10 (ADAM10) may impede the function of antitumor immune cells. Understanding the molecular mechanisms behind this interaction is urgently needed. This study elucidates the mechanism of ADAM10/PD-L1 interaction in the pancreatic adenocarcinoma cell line, PANC-1, using cellular assays, molecular docking, and molecular dynamics (MD) simulations. Cellular assays validated that ADAM10 interacts with PD-L1 and sheds the PD-L1 from the cell surface, generating soluble PD-L1 (sPD-L1). Concurrently, the docking results identified critical residues and potential contact points, providing strong evidence for a stable and specific interaction between ADAM10 and PD-L1. The molecular dynamics (MD) simulations further confirmed the structural integrity of the ADAM10/PD-L1 complex, predicting its compactness and stability. These results elucidate how ADAM10 recognizes and interacts with PD-L1, facilitating its cleavage. Future work can leverage these findings to develop potent cancer immunotherapies that inhibit the ADAM10/PD-L1 interaction and the generation of soluble molecules.