PD-L1 expression by dendritic cells is a key regulator of T-cell immunity in cancer
- 22 June 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Cancer
- Vol. 1 (7), 681-691
- https://doi.org/10.1038/s43018-020-0075-x
Abstract
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.Keywords
Funding Information
- U.S. Department of Health & Human Services | National Institutes of Health (5T32CA078207)
This publication has 68 references indexed in Scilit:
- PD-L1 on host cells is essential for PD-L1 blockade–mediated tumor regressionJCI Insight, 2018
- Host expression of PD-L1 determines efficacy of PD-L1 pathway blockade–mediated tumor regressionJCI Insight, 2018
- The diverse functions of the PD1 inhibitory pathwayNature Reviews Immunology, 2017
- Distinct Cellular Mechanisms Underlie Anti-CTLA-4 and Anti-PD-1 Checkpoint BlockadeCell, 2017
- PD-L1 on tumor cells is sufficient for immune evasion in immunogenic tumors and inhibits CD8 T cell cytotoxicityThe Journal of Experimental Medicine, 2017
- Tumor immune profiling predicts response to anti–PD-1 therapy in human melanomaJCI Insight, 2016
- Overcoming T cell exhaustion in infection and cancerTrends in Immunology, 2015
- Manipulating the PD-1 pathway to improve immunityCurrent Opinion in Immunology, 2013
- Molecular Signature of CD8+ T Cell Exhaustion during Chronic Viral InfectionImmunity, 2007
- Restoring function in exhausted CD8 T cells during chronic viral infectionNature, 2005