B7-H1 signaling is integrated during CD8+ T cell priming and restrains effector differentiation

Gibbons, Rachel; Liu, Xin; Harrington, Susan M.; Krco, Christopher J.; Kwon, Eugene D.; Dong, Haidong

doi:10.1007/s00262-014-1563-6

Cited by 14 publications

(9 citation statements)

References 26 publications

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“…Both PD-1 and CD80 are expressed on CD8 + T cells early during activation and priming by dendritic cells ( 43 – 45 ). Additionally, dendritic cells express cell-surface PD-L1 upon activation by various toll-like receptor ligands ( 40 ).…”

Section: The Role Of Pd-l1 Expressed By Dendritic Cellsmentioning

confidence: 99%

“…Effector CD8 + T cells primed in the absence of PD-L1 signaling exhibit increased cytokine production and enhanced cytotoxic activity as compared to CD8 + T cells primed in the presence of PD-L1 signaling ( 40 , 44 , 45 , 47 , 50 ). Immunization of mice with PD-L1 deficient dendritic cells pulsed with OVA peptide resulted in effector CD8 + T cells that secreted increased levels of IFN-γ and were better able to control B16-OVA tumor growth as compared to effector CD8 + T cells primed by dendritic cells with intact PD-L1 expression ( 40 ).…”

Section: The Role Of Pd-l1 Expressed By Dendritic Cellsmentioning

confidence: 99%

“…Mice injected with anti-PD-L1 prior to HSV-1 infection also demonstrated significantly lower viral load 6 days postinfection ( 47 ). Using a brief in vitro priming model to activate OT-I CD8 + T cells with OVA-presenting dendritic cells with either intact or deficient PD-L1 expression, it was demonstrated that CD8 + T cells primed in the absence of PD-L1 secreted increased levels of IFN-γ and exhibited increased in vivo cytotoxic activity ( 45 ). These studies show that PD-L1 signaling during the priming phase influences the differentiation of effector CD8 + T cells by restraining the acquisition of effector functions.…”

Section: The Role Of Pd-l1 Expressed By Dendritic Cellsmentioning

confidence: 99%

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Functional Expression of Programmed Death-Ligand 1 (B7-H1) by Immune Cells and Tumor Cells

2017

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The programmed death-1 (PD-1) and its ligand PD-L1 (B7-H1) signaling pathway has been the focus of much enthusiasm in the fields of tumor immunology and oncology with recent FDA approval of the anti-PD-1 antibodies pembrolizumab and nivolumab and the anti-PD-L1 antibodies durvalumab, atezolimuab, and avelumab. These therapies, referred to here as PD-L1/PD-1 checkpoint blockade therapies, are designed to block the interaction between PD-L1, expressed by tumor cells, and PD-1, expressed by tumor-infiltrating CD8+ T cells, leading to enhanced antitumor CD8+ T cell responses and tumor regression. The influence of PD-L1 expressed by tumor cells on antitumor CD8+ T cell responses is well characterized, but the impact of PD-L1 expressed by immune cells has not been well defined for antitumor CD8+ T cell responses. Although PD-L1 expression by tumor cells has been used as a biomarker in selection of patients for PD-L1/PD-1 checkpoint blockade therapies, patients whose tumor cells lack PD-L1 expression often respond positively to PD-L1/PD-1 checkpoint blockade therapies. This suggests that PD-L1 expressed by non-malignant cells may also contribute to antitumor immunity. Here, we review the functions of PD-L1 expressed by immune cells in the context of CD8+ T cell priming, contraction, and differentiation into memory populations, as well as the role of PD-L1 expressed by tumor cells in regulating antitumor CD8+ T cell responses.

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Section: The Role Of Pd-l1 Expressed By Dendritic Cellsmentioning

confidence: 99%

Section: The Role Of Pd-l1 Expressed By Dendritic Cellsmentioning

confidence: 99%

Section: The Role Of Pd-l1 Expressed By Dendritic Cellsmentioning

confidence: 99%

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Functional Expression of Programmed Death-Ligand 1 (B7-H1) by Immune Cells and Tumor Cells

2017

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“…Recently, a synergistic action of polyI:C and anti-PD-L1 blockade was demonstrated in mouse models of melanoma [23]. Interestingly, in a mouse model of tumour immunotherapy, the use of PD-L1-deficient DCs pre-activated with polyI:C increased anti-tumour T cell activity [35]. Our results showing that PD-L1 blockade is especially crucial for effective CD8 + T cell responses upon polyI:C treatment go hand-in-hand with these systemic studies suggesting that cancer immunotherapy using polyI:C would strongly benefit from anti-PD-L1 checkpoint blockade.…”

Section: Discussionmentioning

confidence: 99%

TLR3-Induced Maturation of Murine Dendritic Cells Regulates CTL Responses by Modulating PD-L1 Trafficking

2016

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Targeting TLR3 through formulations of polyI:C is widely studied as an adjuvant in cancer immunotherapy. The efficacy of such targeting has been shown to increase in combination with anti-PD-L1 treatment. Nevertheless, the mechanistic details of the effect of polyI:C on DC maturation and the impact on T-DC interactions upon PD-L1 blockade is largely unknown. Here we found that although DC treatment with polyI:C induced a potent inflammatory response including the production of type I interferon, polyI:C treatment of DCs impaired activation of peptide specific CD8+ T cells mainly due to PD-L1. Interestingly, we found that PD-L1 trafficking to the cell surface is regulated in two waves in polyI:C-treated DCs. One induced upon overnight treatment and a second more rapid one, specific to polyI:C treatment, was induced upon CD40 signaling leading to a further increase in surface PD-L1 in DCs. The polyI:C-induced cell surface PD-L1 reduced the times of contact between DCs and T cells, potentially accounting for limited T cell activation. Our results reveal a novel CD40-dependent regulation of PD-L1 trafficking induced upon TLR3 signaling that dictates its inhibitory activity. These results provide a mechanistic framework to understand the efficacy of anti-PD-L1 cancer immunotherapy combined with TLR agonists.

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“…The role of PD-1 as a significant obstacle to antitumor immunity is supported by studies demonstrating that antibody blocking of PD-1 improves T cell activation and reduces tumor progression [7, 9–11] and that antibody blocking of PD-L1 reverse signalling through CD80 prevents T cell anergy [6]. These effects are at least partially due to blocking of PD-L1 on dendritic cells (DC) since the expression of PD-L1 by activated DC limits effector cell differentiation and the generation of CD8 + T cell memory [12]. The critical role of PD-L1 in human cancer was unequivocally established by recent clinical trials in which 19–30 % of patients with certain advanced cancers treated with antibodies to PD-L1 or PD-1 had partial or complete remissions [13, 14].…”

Section: Introductionmentioning

confidence: 99%

Novel strategies for inhibiting PD-1 pathway-mediated immune suppression while simultaneously delivering activating signals to tumor-reactive T cells

Ostrand‐Rosenberg

Horn

Álvarez

2015

Cancer Immunol Immunother

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We previously developed cell-based vaccines as therapeutics for metastatic cancers. The vaccines were aimed at activating type I CD4+T cells and consisted of tumor cells transfected with genes encoding syngeneic MHC class II and CD80 costimulatory molecules, and lacking the MHC II-associated invariant chain. The vaccines showed some efficacy in mice with sarcoma, melanoma, and breast cancer and activated MHC class II syngeneic T cells from breast, lung, and melanoma patients. During the course of the vaccine studies, we observed that CD80 not only costimulated naïve T cells, but also bound to PD-L1 and prevented tumor cell-expressed PD-L1 from binding to its receptor PD-1 on activated T cells. A soluble form of CD80 (CD80-Fc) had the same effect and sustained IFNγ production by both human and murine PD-1+ activated T cells in the presence of PD-L1+ human or mouse tumor cells, respectively. In vitro studies with human tumor cells indicated that CD80-Fc was more effective than antibodies to either PD-1 or PD-L1 in sustaining T cell production of IFNγ. Additionally, in vivo studies with a murine tumor demonstrated that CD80-Fc was more effective than antibodies to PD-L1 in extending survival time. Studies with human T cells blocked for CD28 and with T cells from CD28 knockout mice demonstrated that CD80-Fc simultaneously inhibited PD-L1/PD-1-mediated immune suppression and delivered costimulatory signals to activated T cells, thereby amplifying T cell activation. These results suggest that CD80-Fc may be a useful monotherapy that minimizes PD-1 pathway immune suppression while simultaneously activating tumor-reactive T cells.

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B7-H1 signaling is integrated during CD8+ T cell priming and restrains effector differentiation

Cited by 14 publications

References 26 publications

Functional Expression of Programmed Death-Ligand 1 (B7-H1) by Immune Cells and Tumor Cells

Functional Expression of Programmed Death-Ligand 1 (B7-H1) by Immune Cells and Tumor Cells

TLR3-Induced Maturation of Murine Dendritic Cells Regulates CTL Responses by Modulating PD-L1 Trafficking

Novel strategies for inhibiting PD-1 pathway-mediated immune suppression while simultaneously delivering activating signals to tumor-reactive T cells

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