PD-L1 expression by dendritic cells is a key regulator of T-cell immunity in cancer

• Published in: Nature cancer Vol. 1; no. 7; pp. 681 - 691
• Main Authors: Oh, Soyoung A, Wu, Dai-Chen, Cheung, Jeanne, Navarro, Armando, Xiong, Huizhong, Cubas, Rafael, Totpal, Klara, Chiu, Henry, Wu, Yan, Comps-Agrar, Laetitia, Leader, Andrew M, Merad, Miriam, Roose-Germa, Merone, Warming, Soren, Yan, Minhong, Kim, Jeong M, Rutz, Sascha, Mellman, Ira
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.07.2020
• Subjects: Antibodies; Antigens; B7-H1 Antigen - genetics; Cancer; CD28 Antigens - metabolism; Cells; Dendritic Cells; Experiments; Humans; Immune response; Immunity (Disease); Ligands; Lymphatic system; Lymphocytes; Neoplasms - genetics; Patients; Programmed Cell Death 1 Receptor - genetics; Tumors
• DOI: 10.1038/s43018-020-0075-x

Inhibiting the programmed death-1 (PD-1) pathway is one of the most effective approaches to cancer immunotherapy, but its mechanistic basis remains incompletely understood. Binding of PD-1 to its ligand PD-L1 suppresses T-cell function in part by inhibiting CD28 signaling. Tumor cells and infiltrating myeloid cells can express PD-L1, with myeloid cells being of particular interest as they also express B7-1, a ligand for CD28 and PD-L1. Here we demonstrate that dendritic cells (DCs) represent a critical source of PD-L1, despite being vastly outnumbered by PD-L1 macrophages. Deletion of PD-L1 in DCs, but not macrophages, greatly restricted tumor growth and led to enhanced antitumor CD8 T-cell responses. Our data identify a unique role for DCs in the PD-L1-PD-1 regulatory axis and have implications for understanding the therapeutic mechanism of checkpoint blockade, which has long been assumed to reflect the reversal of T-cell exhaustion induced by PD-L1 tumor cells.