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

Oh, Soyoung; Wu, Dai-Chen; Cheung, Jeanne; Navarro, Alexandre Guida; Xiong, Huizhong; Cubas, Rafael; Tótpál, Klára; Chiu, Henry; Wu, Yan; Comps-Agrar, Laëtitia; Leader, Andrew M.; Mérad, Miriam; Roose-Germa, Merone; Warming, Søren; Yan, Minhong; Kim, Jeong M.; Rutz, Sascha; Mellman, Ira

doi:10.1038/s43018-020-0075-x

Cited by 301 publications

(224 citation statements)

References 70 publications

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“…An interesting fact is that APCs, including DCs, might express PD-1, PD-L1, and CD80 at the same time 38 . Furthermore, PD-L1 is able to interact with PD-1 and CD80 in cis, which makes the working model more complicated [38][39][40][41][42] . In an in vitro system, substantial CD80 expressed on APCs neutralizes PD-L1, thus preventing it from engaging PD-1 to inhibit T cell activation 40 .…”

Section: Discussionmentioning

confidence: 99%

PD-L1 on dendritic cells attenuates T cell activation and regulates response to immune checkpoint blockade

et al. 2020

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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.

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Section: Discussionmentioning

confidence: 99%

PD-L1 on dendritic cells attenuates T cell activation and regulates response to immune checkpoint blockade

et al. 2020

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“…MC21 DCs are characterized by high PD-L1 positivity indicating that this subset is T cell suppressive(Oh et al, 2020). Although the shift was small, MC21 was significantly increased in the obese E0771 group.…”

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confidence: 92%

High dimensional immunotyping of the obese tumor microenvironment reveals model specific adaptation

Wogsland

Lien

Pedersen

et al. 2020

Preprint

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Obesity is a disease characterized by chronic low-grade systemic inflammation and has been causally linked to the development of 13 cancer types. Several studies have been undertaken to determine if tumors evolving in obese environments adapt differential interactions with immune cells and if this can be connected to disease outcome. Most of these studies have been limited to single cell lines and tumor models and analysis of limited immune cell populations. Given the multicellular complexity of the immune system and its dysregulation in obesity, we applied high-dimensional suspension mass cytometry to investigate how obesity affects tumor immunity. We used a 36-marker immune-focused mass cytometry panel to interrogate the immune landscape of orthotopic syngeneic mouse models of pancreatic and breast cancer. Unanchored batch correction was implemented to enable simultaneous analysis of tumor cohorts to uncover the immunotypes of each cancer model and reveal remarkably model-specific immune regulation. In the E0771 breast cancer model, we demonstrate an important link to obesity with an increase in two T cell suppressive cell types and a decrease in CD8 T-cells.

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“…Additionally, dendritic cell and natural killer (NK) cell infiltration were found to be significantly associated with pnSTING high tumors, in keeping with dendritic cells as a key source of PD-L1 and in promoting T-cell responses 31 . Importantly, gene expression of STING did not strongly correlate with pnSTING scores in ER+ tumors (Fig.…”

Section: Perinuclear Sting Expression Correlates With the Immune Landmentioning

confidence: 74%

The clinical and molecular significance associated with STING signaling in estrogen receptor-positive early breast cancer

Parkes

Humphries

Gilmore

et al. 2020

Preprint

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STING signaling in cancer is a crucial component of response to immunotherapy and other anti-cancer treatments. Conversely, STING signaling can promote tumor invasion and metastasis. Currently, there is no robust method of measuring STING activation in cancer. Here, we describe an immunohistochemistry-based assay with digital pathology assessment of STING in tumor cells. Using this novel approach, we identify perinuclear-localized expression of STING (pnSTING) in estrogen receptor-positive (ER+) breast cancer as an independent predictor of good prognosis, associated with immune cell infiltration and upregulation of immune checkpoints. Tumors with low pnSTING are immunosuppressed with increased infiltration of “M2” -polarised macrophages. In ER-disease, pnSTING does not have a significant prognostic role, and STING appears to be uncoupled from interferon responses. Importantly, a gene signature defining low pnSTING expression in ER+ disease is predictive of poor prognosis in independent datasets. Low pnSTING is associated with chromosomal instability, MYC amplification and mTOR signaling, suggesting novel therapeutic approaches for this subgroup.

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

Cited by 301 publications

References 70 publications

PD-L1 on dendritic cells attenuates T cell activation and regulates response to immune checkpoint blockade

PD-L1 on dendritic cells attenuates T cell activation and regulates response to immune checkpoint blockade

High dimensional immunotyping of the obese tumor microenvironment reveals model specific adaptation

The clinical and molecular significance associated with STING signaling in estrogen receptor-positive early breast cancer

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