B7-H1 maintains the polyclonal T cell response by protecting dendritic cells from cytotoxic T lymphocyte destruction

Chen, Ling; Azuma, Takeshi; Yu, Weiwei; Xu, Zheng; Luo, Liqun

doi:10.1073/pnas.1722043115

Cited by 25 publications

(14 citation statements)

References 36 publications

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“…Specifically, cDC1s, which are particularly important for the priming and activation of CD8 + T cells, upregulate PD-L1 expression upon antigen uptake. Consistent with a recent study, we found that PD-L1 on DCs protects them from killing by cytotoxic T lymphocytes, yet dampens the antitumor immune responses 37 . In addition, PD-L1 upregulation on cDC1s is mediated by IFN-γ produced by activated T cells.…”

Section: Discussionsupporting

confidence: 92%

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: Discussionsupporting

confidence: 92%

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

et al. 2020

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“…In the context of these observations, it seems reasonable to combine local therapies with anti-PD therapy to neutralize the immunosuppressive mechanisms developed in the TME as long as the B7-H1/PD-1 pathway is one of the major immunosuppressive mechanisms. It is also possible that this combination may deviate the T cell response against viral antigens instead of tumor antigens due to possible immunological dominancy by anti-PD therapy (Martínez-Usatorre et al, 2018; Chen et al, 2018). Local treatment, on the other hand, has shown to be an effective approach to increase T cell infiltration into tumors.…”

Section: The Principles To Combine Other Therapeutics With Anti-pd Thmentioning

confidence: 99%

A Paradigm Shift in Cancer Immunotherapy: From Enhancement to Normalization

Sanmamed

Chen

2018

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Harnessing an antitumor immune response has been a fundamental strategy in cancer immunotherapy. For over a century, efforts have primarily focused on amplifying immune activation mechanisms that are employed by humans to eliminate invaders such as viruses and bacteria. This “immune enhancement” strategy often results in rare objective responses and frequent immune-related adverse events (irAEs). However, in the last decade, cancer immunotherapies targeting the B7-H1/PD-1 pathway (anti-PD therapy), have achieved higher objective response rates in patients with much fewer irAEs. This more beneficial tumor response-to-toxicity profile stems from distinct mechanisms of action that restore tumor-induced immune deficiency selectively in the tumor microenvironment, here termed “immune normalization,” which has led to its FDA approval in more than 10 cancer indications and facilitated its combination with different therapies. In this article, we wish to highlight the principles of immune normalization and learn from it, with the ultimate goal to guide better designs for future cancer immunotherapies.

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“…Следует отметить, что роль В7-Н1 в биологии DC до конца не ясна. Показано, в частности, что молекула В7-Н1, ýкспрессируемая на DC, участвует не только в индукции апоптоза и анергии Т-клеток [18], но обладает также протективной функцией, обеспечивая устойчивость DC к лизису со стороны цитотоксических Т-клеток [19]. В настоящем исследовании подавляющая часть интактных CD16 − Мо-DC и CD16 + Мо-DC коýкспрессировали В7-Н1 и CD86 (см.…”

Section: Discussionunclassified

Phenotype and functions of human dendritic cells derived from CD14+ monocyte subsets opposed to CD16 expression

et al. 2019

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The aim of the study was to analyze the relationship between monocyte subpopulations and phenotype/ functions of monocyte-derived dendritic cells (DCs), as well as DC sensitivity to the tolerogenic effect of dexamethasone.Materials and methods. The study included 15 healthy donors. DCs were generated by cultivating enriched fractions of CD14+ monocytes with or without CD16+cell depletion (CD16-Mo-DCs or CD16+Mo-DCs, respectively) in the presence of interferon alpha (IFNα) and granulocyte-macrophage colony-stimulating factor (GM-CSF). Monocyte subpopulations were obtained by immunomagnetic negative selection.Results. CD16+Mo-DCs were characterized by higher percentage of mature (CD83+CD14-) and lower number of semi-mature (CD14+CD83+) cells, but were similar to CD16-Mo-DCs by HLA-DR and CD86 expression, involved in the presentation of antigens and activation of naive T-cells. and also to co-inhibitory/ tolerogenic molecules B7-H1 and TLR-2. CD16+Mo-DCs displayed higher allostimulatory activity, which was positively correlated with CD86 expression (rS = 0.69; p = 0.027) and negatively – with TLR-2 expression (rS = -0.72; p = 0.1). Allostimulatory activity of CD16-Mo-DCs was positively correlated with the number of mature CD14-CD83+DCs and semi-mature CD14+CD83+DCs. Addition of dexamethasone (10-6 M) into CD16-Mo-DCs and CD16+Mo-DCs cultures led to the delay of DC maturation, the decrease of CD86 and the increase of TLR-2 expression, as well as the increase of cells with co-inhibitory CD86- B7-H1+ phenotype that was positively correlated with the reduction of DC allostimulatory activity. The decrease of CD86+/TLR-2+ index in CD16+Mo-DC population was due to the reduction of CD86+DCs and in CD16-Mo-DC population – to the increase of TLR-2+cells. Dexamethasone possessed higher inhibitory effect on DC maturation in the CD16+Mo-DC cultures.Conclusion. CD14+ monocytes, both contained and depleted by CD16+ cells, can differentiate into DCs when cultured with IFNα. The presence of CD16+ cells in whole blood monocyte pool is associated with generation of DCs showed a more mature phenotype and higher allostimulatory activity. Both CD16- and CD16+ monocyte-derived DCs are sensitive to suppressive effect of dexamethasone. However, dexamethasone tolerogenic effect involves different mechanisms in CD16-Mo-DCs and CD16+Mo-DCs.

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B7-H1 maintains the polyclonal T cell response by protecting dendritic cells from cytotoxic T lymphocyte destruction

Cited by 25 publications

References 36 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

A Paradigm Shift in Cancer Immunotherapy: From Enhancement to Normalization

Phenotype and functions of human dendritic cells derived from CD14+ monocyte subsets opposed to CD16 expression

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