PD-L1/B7H-1 Inhibits the Effector Phase of Tumor Rejection by T Cell Receptor (TCR) Transgenic CD8+ T Cells

Blank, Christian U.; Brown, Ian E.; Peterson, Amy; Spiotto, M.T.; Iwai, Yoshiko; Honjo, Tasuku; Gajewski, Thomas F.

doi:10.1158/0008-5472.can-03-3259

Cited by 697 publications

(542 citation statements)

References 40 publications

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“…One possibility that could explain why LIGHT treatment does not work on large tumors is due to the fact that LIGHT increases the level of IFN-γ ( Figure 5G), which can also promote PD-L1 upregulation as part of the adaptive resistance mechanism (Blank et al, 2004). We hypothesized that LIGHT might trigger inhibitory signals as a negative feedback mechanism, which in turn can dampen the initial antitumor effects on large tumors.…”

Section: Light Overcomes Tumor Resistance To Anti-pd-l1 By Increasingmentioning

confidence: 99%

Facilitating T Cell Infiltration in Tumor Microenvironment Overcomes Resistance to PD-L1 Blockade

Tang¹,

Wang²,

Chlewicki³

et al. 2016

Cancer Cell

147

143

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SUMMARYImmune checkpoint blockade therapies fail to induce responses in majority of cancer patients; so how to increase the objective response rate becomes an urgent challenge. Here we demonstrate that sufficient T cell infiltration in tumor tissues is a prerequisite for response to PD-L1 blockade. Targeting tumors with tumor necrosis factor superfamily member LIGHT activates lymphotoxin beta receptor signaling, leading to the production of chemokines that recruit massive numbers of T cells. Furthermore, targeting non-T cell-inflamed tumor tissues by antibody-guided LIGHT creates a T cell-inflamed microenvironment and overcomes tumor resistance to checkpoint blockade. Our data indicates that targeting LIGHT might be a potent strategy to increase the responses to checkpoint blockades and other immunotherapies in non-T cell-inflamed tumors.

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Section: Light Overcomes Tumor Resistance To Anti-pd-l1 By Increasingmentioning

confidence: 99%

Facilitating T Cell Infiltration in Tumor Microenvironment Overcomes Resistance to PD-L1 Blockade

Tang¹,

Wang²,

Chlewicki³

et al. 2016

Cancer Cell

147

143

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“…Depending on the model system, PD-L1 and PD-L2 were initially reported to have inhibitory or stimulatory effects on T cell responses (13,14). Recent reports on PD-L1 using knockout mice or in vivo studies with blocking anti-PD-L1 mAbs have been consistent with an inhibitory role for PD-L1 (13,16,(21)(22)(23)(24)(25)(26). Recent reports on PD-L2 using knockout mice or blocking mAbs still find opposing functions (27,28).…”

Section: Pd-1:pd-l1 Interactionsmentioning

confidence: 99%

PD-1:PD-L1 Interactions Contribute to the Functional Suppression of Virus-Specific CD8+ T Lymphocytes in the Liver

Maier

Isogawa

Freeman

et al. 2007

The Journal of Immunology

215

172

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Mechanisms contributing to the development of chronic viral infections, including chronic hepatitis B virus (HBV) infections, are not well understood. We have shown recently that production of IFN-γ, an important antiviral cytokine, by HBV-specific CTLs is rapidly induced when they enter the liver of HBV transgenic mice, and then rapidly suppressed, despite the continued presence of Ag. Suppression of IFN-γ production by the CTLs coincides with the up-regulation of programmed cell death (PD)-1, a cell surface signaling molecule known to inhibit T cell function. To determine whether PD-1 plays a role in the functional suppression of IFN-γ secretion by CTLs, we treated HBV transgenic mice with blocking Abs specific for PD ligand (PD-L)1, the most widely expressed PD-1 ligand, and adoptively transferred HBV-specific CTLs. Treatment with anti-PD-L1 Abs resulted in a delay in the suppression of IFN-γ-producing CTLs and a concomitant increase in the absolute number of IFN-γ-producing CTLs in the liver. These results indicate that PD-1:PD-L1 interactions contribute to the suppression of IFN-γ secretion observed following Ag recognition in the liver. Blockade of inhibitory pathways such as PD-1:PD-L1 may reverse viral persistence and chronic infection in cases in which the CTL response is suppressed by this mechanism.

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“…Anti-CTLA-4 treatment has been trialled in melanoma and other cancers with some evidence of clinical efficacy (Wolchok and Saenger, 2008;Yuan et al, 2008). The expression of PD-L1 (B7-H1), a ligand for PD-1, is upregulated by IFN-g (Blank et al, 2004) and has been observed in many tumour types, often being associated with a poor prognosis (Zou and Chen, 2008). PD-1/PD-L1 interactions impair anti-tumour T-cell responses in mice, which is reversed in PD-1-deficient mice or by blocking PD1 (Blank et al, 2004).…”

Section: Activated T Cells May Be Switched Off By Some Tumoursmentioning

confidence: 99%

“…The expression of PD-L1 (B7-H1), a ligand for PD-1, is upregulated by IFN-g (Blank et al, 2004) and has been observed in many tumour types, often being associated with a poor prognosis (Zou and Chen, 2008). PD-1/PD-L1 interactions impair anti-tumour T-cell responses in mice, which is reversed in PD-1-deficient mice or by blocking PD1 (Blank et al, 2004). Mechanistically, expression of PD-L1 by tumours induces T-cell apoptosis (Dong et al, 2002), induces production of IL-10 and may mediate regulatory T cell (Treg)-suppressive activity (Zou and Chen, 2008).…”

Section: Activated T Cells May Be Switched Off By Some Tumoursmentioning

confidence: 99%

Harnessing the immune response to treat cancer

et al. 2010

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It is well established that the immune system has the capacity to attack malignant cells. During malignant transformation cells acquire numerous molecular and biochemical changes that render them potentially vulnerable to immune cells. Yet it is self-evident that a growing tumour has managed to evade these host defence mechanisms. The exact ways in which the immune system interacts with tumour cells and how cancers are able to escape immunological eradication have only recently started to be fully elucidated. Understanding the relationship between the tumour and the anti-tumour immune response and how this can be altered with conventional treatments and immune-targeted therapies is crucial to developing new treatments for patients with cancer. In this review, focusing on the anti-tumour T-cell response, we summarize our understanding of how tumours, cancer treatments and the immune system interact, how tumours evade the immune response and how this process could be manipulated for the benefit of patients with cancer.

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PD-L1/B7H-1 Inhibits the Effector Phase of Tumor Rejection by T Cell Receptor (TCR) Transgenic CD8+ T Cells

Abstract: ABSTRACT

Cited by 697 publications

References 40 publications

Facilitating T Cell Infiltration in Tumor Microenvironment Overcomes Resistance to PD-L1 Blockade

Facilitating T Cell Infiltration in Tumor Microenvironment Overcomes Resistance to PD-L1 Blockade

PD-1:PD-L1 Interactions Contribute to the Functional Suppression of Virus-Specific CD8+ T Lymphocytes in the Liver

Harnessing the immune response to treat cancer

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