Regulation and Function of the PD-L1 Checkpoint

Sun, Chong; Mezzadra, Riccardo; Schumacher, Ton N.

doi:10.1016/j.immuni.2018.03.014

Cited by 1,540 publications

(1,467 citation statements)

References 228 publications

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“…PD‐L1 expression is regulated via multiple mechanisms. Several transcription factors and signaling pathways including Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3), pEGFR signaling, mitogen‐activated protein kinase (MAPK) pathway and MYC regulate PD‐L1 expression on cancer cells . We first determined the effect of AF treatment on pEGFR, pERK1/2 and MYC levels as a readout of MAPK pathway and pSTAT3 levels in TNBC cells.…”

Section: Resultsmentioning

confidence: 99%

Therapeutic cooperation between auranofin, a thioredoxin reductase inhibitor and anti‐PD‐L1 antibody for treatment of triple‐negative breast cancer

Raninga

Lee

Sinha

et al. 2019

Intl Journal of Cancer

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Triple‐negative breast cancer (TNBCs) is a very aggressive and lethal form of breast cancer with no effective targeted therapy. Neoadjuvant chemotherapies and radiotherapy remains a mainstay of treatment with only 25–30% of TNBC patients responding. Thus, there is an unmet clinical need to develop novel therapeutic strategies for TNBCs. TNBC cells have increased intracellular oxidative stress and suppressed glutathione, a major antioxidant system, but still, are protected against higher oxidative stress. We screened a panel of antioxidant genes using the TCGA and METABRIC databases and found that expression of the thioredoxin pathway genes is significantly upregulated in TNBC patients compared to non‐TNBC patients and is correlated with adverse survival outcomes. Treatment with auranofin (AF), an FDA‐approved thioredoxin reductase inhibitor caused specific cell death and impaired the growth of TNBC cells grown as spheroids. Furthermore, AF treatment exerted a significant in vivo antitumor activity in multiple TNBC models including the syngeneic 4T1.2 model, MDA‐MB‐231 xenograft and patient‐derived tumor xenograft by inhibiting thioredoxin redox activity. We, for the first time, showed that AF increased CD8+Ve T‐cell tumor infiltration in vivo and upregulated immune checkpoint PD‐L1 expression in an ERK1/2‐MYC‐dependent manner. Moreover, combination of AF with anti‐PD‐L1 antibody synergistically impaired the growth of 4T1.2 primary tumors. Our data provide a novel therapeutic strategy using AF in combination with anti‐PD‐L1 antibody that warrants further clinical investigation for TNBC patients.

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Section: Resultsmentioning

confidence: 99%

Therapeutic cooperation between auranofin, a thioredoxin reductase inhibitor and anti‐PD‐L1 antibody for treatment of triple‐negative breast cancer

Raninga

Lee

Sinha

et al. 2019

Intl Journal of Cancer

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show abstract

“…However, while PD-L1 regulation has been extensively studied in cancer cells 1 , the regulation of PD-L1 in stromal cells is less well understood. Also, since the stroma in PDAC tumors predominates 5,6 , it is very likely that cytolytic T cells in PDAC tumors will encounter PSCs.…”

Section: Discussionmentioning

confidence: 99%

Interplay between interferon regulatory factor 1 and BRD4 in the regulation of PD-L1 in pancreatic stellate cells

Ebine

Kumar

Pham

et al. 2018

Sci Rep

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The fibrotic reaction is a characteristic feature of human pancreatic ductal adenocarcinoma (PDAC) tumors. It is associated with activation and proliferation of pancreatic stellate cells (PSCs), which are key regulators of fibrosis in vivo. While there is increasing interest in the regulation of PD-L1 expression in cancer and immune cells, the expression and regulation of PD-L1 in other stromal cells, such as PSCs, has not been fully evaluated. Here we show that PSCs in vitro express higher PD-L1 mRNA and protein levels compared to the levels present in PDAC cells. We show that inhibitors targeting bromodomain and extra-terminal (BET) proteins and BRD4 knockdown decrease interferon-γ (IFN-γ)-induced PD-L1 expression in PSCs. We also show that c-MYC, one of the well-established targets of BET inhibitors, does not mediate IFN-γ-regulated PD-L1 expression in PSCs. Instead we show that interferon regulatory factor 1 (IRF1) mediates IFN-γ-induced PD-L1 expression in PSCs. Finally, while we show that BET inhibitors do not regulate IFN-γ-induced IRF1 expression in PSCs, BET inhibitors decrease binding of IRF1 and BRD4 to the PD-L1 promoter. Together, these results demonstrate the interplay between IRF1 and BRD4 in the regulation of PD-L1 in PSCs.

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“…1 However, immune-checkpoint blockade is reportedly efficacious in patients with cancer, [2][3][4][5] and inhibitory antibodies (Abs) against PD-1, PD-L1 and CTLA-4 are approved for the treatment of a growing list of cancers. 6,8 The efficacy of immune-checkpoint blockade is reportedly associated with the immunogenicity of the tumour. 6,8 The efficacy of immune-checkpoint blockade is reportedly associated with the immunogenicity of the tumour.…”

Section: Introductionmentioning

confidence: 99%

An agonistic anti‐Toll‐like receptor 4 monoclonal antibody as an effective adjuvant for cancer immunotherapy

et al. 2019

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Summary Immune‐checkpoint blockade antibodies have been approved for the treatment of cancer. However, poorly immunogenic tumours are less responsive to such therapies. Agonistic anti‐Toll‐like receptor 4 (TLR4) monoclonal antibodies (mAbs) activate only cell‐surface TLR4; in contrast, lipopolysaccharide (LPS) activates both TLR4 and intracellular inflammatory caspases. In this study, we investigated the adjuvant activity of an anti‐TLR4 mAb in T‐cell‐mediated antitumour immunity. The anti‐TLR4 mAb induced the activation of antigen‐specific T‐cells in adoptive transfer studies. The growth of ovalbumin (OVA)‐expressing tumours was significantly suppressed by administration of OVA and the anti‐TLR4 mAb in combination, but not individually. The antitumour effect of anti‐PD‐1 mAb was enhanced in mice administered with OVA plus the anti‐TLR4 mAb. The OVA‐specific IFN‐γ‐producing CD8 T‐cells were induced by administration of OVA and the anti‐TLR4 mAb. The suppression of tumour growth was diminished by depletion of CD8, but not CD4, T‐cells. The inflammatory response to the anti‐TLR4 mAb was of significantly lesser magnitude than that to LPS, as assessed by NF‐κB activation and production of TNF‐α, IL‐6 and IL‐1β. Administration of LPS (at a dose that elicited levels of proinflammatory cytokines comparable to those by the anti‐TLR4 mAb) plus OVA induced no or less‐marked activation of OVA‐specific T‐cells and failed to suppress tumour growth in mice. In conclusion, the agonistic anti‐TLR4 mAb induces potent CD8 T‐cell‐dependent antitumour immunity and an inflammatory response of lesser magnitude than does LPS. The agonistic anti‐TLR4 mAb has potential as an adjuvant for use in vaccines against cancer.

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Regulation and Function of the PD-L1 Checkpoint

Cited by 1,540 publications

References 228 publications

Therapeutic cooperation between auranofin, a thioredoxin reductase inhibitor and anti‐PD‐L1 antibody for treatment of triple‐negative breast cancer

Therapeutic cooperation between auranofin, a thioredoxin reductase inhibitor and anti‐PD‐L1 antibody for treatment of triple‐negative breast cancer

Interplay between interferon regulatory factor 1 and BRD4 in the regulation of PD-L1 in pancreatic stellate cells

An agonistic anti‐Toll‐like receptor 4 monoclonal antibody as an effective adjuvant for cancer immunotherapy

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