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PD-L1 on dendritic cells attenuates T cell activation and regulates response to immune checkpoint blockade
Qi Peng1,2, Xiangyan Qiu3, Zihan Zhang1
1School of Pharmaceutical Sciences, Tsinghua University, 100084, Beijing, China.
Abstract:
Immune checkpoint blockade therapies have shown clinical promise in a variety of cancers, but how tumor-infiltrating T cells are activated remains unclear. In this study, we explore the functions of PD-L1 on dendritic cells (DCs), which highly express PD-L1. We observe that PD-L1 on DC plays a critical role in limiting T cell responses. Type 1 conventional DCs are essential for PD-L1 blockade and they upregulate PD-L1 upon antigen uptake. Upregulation of PD-L1 on DC is mediated by type II interferon. While DCs are the major antigen presenting cells for cross-presenting tumor antigens to T cells, subsequent PD-L1 upregulation protects them from killing by cytotoxic T lymphocytes, yet dampens the antitumor responses. Blocking PD-L1 in established tumors promotes re-activation of tumor-infiltrating T cells for tumor control. Our study identifies a critical and dynamic role of PD-L1 on DC, which needs to be harnessed for better invigoration of antitumor immune responses.
Insights
Immune checkpoint blockade therapies show promise, but T cell activation in tumors is unclear. This study reveals PD-L1 on dendritic cells (DCs) limits T cell responses, and blocking PD-L1 can reinvigorate anti-tumor immunity.
Area of Science:
- Immunology
- Cancer Biology
- Cellular Biology
Background:
- Immune checkpoint blockade (ICB) therapies are effective in treating various cancers.
- The precise mechanisms of tumor-infiltrating T cell activation during ICB remain incompletely understood.
- Dendritic cells (DCs) highly express PD-L1 and are crucial antigen-presenting cells in the tumor microenvironment.
Purpose of the Study:
- To investigate the role of PD-L1 expressed on dendritic cells (DCs) in regulating anti-tumor T cell responses.
- To elucidate the mechanisms by which PD-L1 on DCs influences T cell activation and tumor immunity.
- To explore the therapeutic potential of targeting PD-L1 on DCs for enhancing anti-tumor immune responses.
Main Methods:
- Analysis of PD-L1 expression on dendritic cells (DCs) in tumor models.
- Investigating the function of PD-L1 on DCs in modulating T cell activation and proliferation.
- Utilizing PD-L1 blockade strategies in established tumor models to assess impact on T cell responses and tumor control.
- Examining the role of type II interferon in mediating PD-L1 upregulation on DCs.
Main Results:
- PD-L1 expressed on DCs plays a critical role in suppressing T cell responses within the tumor microenvironment.
- Type 1 conventional DCs upregulate PD-L1 upon antigen uptake, a process mediated by type II interferon.
- PD-L1 upregulation on DCs protects them from cytotoxic T lymphocyte-mediated killing but dampens overall anti-tumor immunity.
- Blocking PD-L1 in established tumors leads to the re-activation of tumor-infiltrating T cells and promotes tumor control.
Conclusions:
- PD-L1 on dendritic cells exerts a dynamic and inhibitory effect on anti-tumor T cell immunity.
- Targeting PD-L1 on DCs is a promising strategy to enhance the efficacy of cancer immunotherapies.
- Harnessing the function of PD-L1 on DCs is crucial for invigorating anti-tumor immune responses and improving clinical outcomes.
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