Interactions between PD-1 and PD-L1 promote tolerance by blocking the TCR–induced stop signal

Fife, Brian T.; Pauken, Kristen E.; Eagar, Todd N.; Obu, Takashi; Wu, Jenny Q.; Tang, Qizhi; Azuma, Miyuki; Krummel, Matthew F.; Bluestone, Jeffrey A.

doi:10.1038/ni.1790

Cited by 639 publications

(612 citation statements)

References 49 publications

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“…23,25,26). One study reported no changes in the fast motility of tolerized diabetogenic BDC2.5 CD4 þ T cells after treatment with a-CTLA-4 antibodies in lymph nodes or pancreatic islets, unlike the T-cell stopping and subsequent T-cell activation triggered by a-PD-1 or a-PD-L1 antibody blockade (25). Of note, the authors described this antibody-induced T-cell stopping phenomenon as blockade of the tolerance mediated by the PD-1 and PD-L1 reversal of the TCR-induced stop signal (25).…”

Section: Discussionmentioning

confidence: 99%

Cytotoxic T Lymphocyte Antigen-4 Blockade Enhances Antitumor Immunity by Stimulating Melanoma-Specific T-cell Motility

Pentcheva-Hoang

Simpson

Montalvo-Ortiz

et al. 2014

Cancer Immunology Research

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It is now clear that anti-CTLA-4 (a-CTLA-4) antibodies stimulate tumor immunity either by relieving inhibition of effector T-cell function or by depletion of regulatory T cells (Treg). Several recent reports, however, have suggested that these antibodies may deliver a "go" signal to effector T cells, thus interrupting T-cell receptor signaling and subsequent T-cell activation. We examined the behavior of melanoma-specific CD8 þ pmel-1 T cells in the B16/BL6 mouse model using intravital microscopy. Pmel-1 velocities in progressively growing tumors were lower than their velocities in tumors given a therapeutic combination that included a-CTLA-4 antibodies, suggesting that successful immunotherapy correlates with greater T-cell motility. When a-CTLA-4 antibodies were injected during imaging, the velocities of pmel-1 T cells in tumor-draining lymph nodes also increased. Because a-CTLA-4 Fab fragments had the same effect as the intact antibody, the higher T-cell motility does not seem to be due to CTLA-4 inhibitory signaling but rather to the release of nonproductive stable interactions between tumor-infiltrating T cells and tumor targets or antigen-presenting cells subsequent to CTLA-4 blockade. This phenomenon resembles the recently described reversal of the antiviral T-cell motility paralysis by programmed death 1 (PD-1)-specific antibodies during T-cell exhaustion in persistent viral infections. Cancer Immunol Res; 2(10); 970-80. Ó2014 AACR.

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Section: Discussionmentioning

confidence: 99%

Cytotoxic T Lymphocyte Antigen-4 Blockade Enhances Antitumor Immunity by Stimulating Melanoma-Specific T-cell Motility

Pentcheva-Hoang

Simpson

Montalvo-Ortiz

et al. 2014

Cancer Immunology Research

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“…Coinhibitory molecules like CTLA-4 and PD-1 interfere with T cell priming and there is evidence that they transmit the initial T cell migratory stop signal and thus regulate time and/or strength of the priming interaction between T cells and DCs (52,53). To investigate whether these molecules block Ag-independent proliferation of CD4 + T cells, we transferred 2-d-primed CFSE-labeled AND and OT1 T cells into Ag-free hosts, which had received blocking mAbs against CTLA-4, PD-1, or PD-L1 (Fig.…”

Section: Ag-independent Cd4 + T Cell Proliferation Is Not Affected Bymentioning

confidence: 99%

Differential Kinetics of Antigen Dependency of CD4+ and CD8+ T Cells

Rabenstein

Ellwart

et al. 2014

The Journal of Immunology

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Ag recognition via the TCR is necessary for the expansion of specific T cells that then contribute to adaptive immunity as effector and memory cells. Because CD4+ and CD8+ T cells differ in terms of their priming APCs and MHC ligands we compared their requirements of Ag persistence during their expansion phase side by side. Proliferation and effector differentiation of TCR transgenic and polyclonal mouse T cells were thus analyzed after transient and continuous TCR signals. Following equally strong stimulation, CD4+ T cell proliferation depended on prolonged Ag presence, whereas CD8+ T cells were able to divide and differentiate into effector cells despite discontinued Ag presentation. CD4+ T cell proliferation was neither affected by Th lineage or memory differentiation nor blocked by coinhibitory signals or missing inflammatory stimuli. Continued CD8+ T cell proliferation was truly independent of self-peptide/MHC-derived signals. The subset divergence was also illustrated by surprisingly broad transcriptional differences supporting a stronger propensity of CD8+ T cells to programmed expansion. These T cell data indicate an intrinsic difference between CD4+ and CD8+ T cells regarding the processing of TCR signals for proliferation. We also found that the presentation of a MHC class II–restricted peptide is more efficiently prolonged by dendritic cell activation in vivo than a class I bound one. In summary, our data demonstrate that CD4+ T cells require continuous stimulation for clonal expansion, whereas CD8+ T cells can divide following a much shorter TCR signal.

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“…Normally, this would be considered a disadvantageous effect of HDAC inhibition because PD-L1 is involved in promoting tolerance and decreasing immune surveillance. 61,62 However, the data from our study suggest the enhanced PD-L1 levels on tumor cells could increase the accumulation of anti-PD-L1 antibody in the TME and subsequently enhance ADCC tumor cell lysis (Figures 2, 4, and 5). This concept could be applied to other antibody therapies that target PD-L1 and mediate ADCC, such as M7824, which combines an anti-PD-L1 antibody with a TGFβ Trap, increasing the amount of the bifunctional antibody conjugate in the TME (Figure 4C).…”

Section: Discussionmentioning

confidence: 70%

Epigenetic priming of both tumor and NK cells augments antibody-dependent cellular cytotoxicity elicited by the anti-PD-L1 antibody avelumab against multiple carcinoma cell types

et al. 2018

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Checkpoint inhibitors targeting the PD-1/PD-L1 axis are promising immunotherapies shown to elicit objective responses against multiple tumor types, yet these agents fail to benefit most patients with carcinomas. This highlights the need to develop effective therapeutic strategies to increase responses to PD-1/PD-L1 blockade. Histone deacetylase (HDAC) inhibitors in combination with immunotherapies have provided preliminary evidence of anti-tumor effects. We investigated here whether exposure of either natural killer (NK) cells and/or tumor cells to two different classes of HDAC inhibitors would augment (a) NK cell‒mediated direct tumor cell killing and/or (b) antibody-dependent cellular cytotoxicity (ADCC) using avelumab, a fully human IgG1 monoclonal antibody targeting PD-L1. Treatment of a diverse array of human carcinoma cells with a clinically relevant dose of either the pan-HDAC inhibitor vorinostat or the class I HDAC inhibitor entinostat significantly enhanced the expression of multiple NK ligands and death receptors resulting in enhanced NK cell‒mediated lysis. Moreover, HDAC inhibition enhanced tumor cell PD-L1 expression both in vitro and in carcinoma xenografts. These data demonstrate that treatment of a diverse array of carcinoma cells with two different classes of HDAC inhibitors results in enhanced NK cell tumor cell lysis and avelumab-mediated ADCC. Furthermore, entinostat treatment of NK cells from healthy donors and PBMCs from cancer patients induced an activated NK cell phenotype, and heightened direct and ADCC-mediated healthy donor NK lysis of multiple carcinoma types. This study thus extends the mechanism and provides a rationale for combining HDAC inhibitors with PD-1/PD-L1 checkpoint blockade to increase patient responses to anti-PD-1/PD-L1 therapies.

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Interactions between PD-1 and PD-L1 promote tolerance by blocking the TCR–induced stop signal

Cited by 639 publications

References 49 publications

Cytotoxic T Lymphocyte Antigen-4 Blockade Enhances Antitumor Immunity by Stimulating Melanoma-Specific T-cell Motility

Cytotoxic T Lymphocyte Antigen-4 Blockade Enhances Antitumor Immunity by Stimulating Melanoma-Specific T-cell Motility

Differential Kinetics of Antigen Dependency of CD4+ and CD8+ T Cells

Epigenetic priming of both tumor and NK cells augments antibody-dependent cellular cytotoxicity elicited by the anti-PD-L1 antibody avelumab against multiple carcinoma cell types

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