PD-L1 expression by dendritic cells is a key regulator of T-cell immunity in cancer
Soyoung A Oh1, Dai-Chen Wu1,2, Jeanne Cheung1
1Genentech, Inc., South San Francisco, CA, USA.
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.
Insights
Dendritic cells (DCs) are key sources of PD-L1, suppressing anti-tumor immunity. Removing PD-L1 from DCs, not macrophages, enhanced T-cell responses and restricted tumor growth, revealing a novel therapeutic target.
Area of Science:
- Immunology
- Cancer Biology
- Cellular Signaling
Background:
- The programmed death-1 (PD-1) pathway is crucial in cancer immunotherapy, yet its mechanisms are not fully understood.
- PD-1/PD-L1 interaction suppresses T-cell function, partly by inhibiting CD28 signaling.
- Tumor and myeloid cells express PD-L1, with myeloid cells also expressing B7-1, a CD28 ligand.
Purpose of the Study:
- To investigate the specific role of dendritic cells (DCs) as a source of PD-L1 in the tumor microenvironment.
- To determine the impact of PD-L1 expression in DCs versus macrophages on tumor growth and T-cell responses.
- To elucidate the mechanistic basis of PD-1 pathway inhibition in cancer immunotherapy.
Main Methods:
- Utilized genetic deletion models to specifically remove PD-L1 from dendritic cells (DCs) or macrophages.
- Assessed tumor growth kinetics following PD-L1 deletion in distinct myeloid cell populations.
- Quantified CD8+ T-cell responses to evaluate the impact on anti-tumor immunity.
Main Results:
- Dendritic cells (DCs) were identified as a critical source of PD-L1, even when outnumbered by PD-L1+ macrophages.
- Selective deletion of PD-L1 in DCs, but not macrophages, significantly inhibited tumor growth.
- PD-L1 deletion in DCs led to markedly enhanced anti-tumor CD8+ T-cell responses.
Conclusions:
- Dendritic cells play a unique and critical role in regulating the PD-1/PD-L1 axis within the tumor microenvironment.
- Targeting PD-L1 specifically on DCs offers a promising strategy for enhancing cancer immunotherapy efficacy.
- These findings challenge the assumption that PD-1 blockade primarily reverses T-cell exhaustion induced by tumor cell PD-L1.
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