Expression of PD-L1 on Canine Tumor Cells and Enhancement of IFN-γ Production from Tumor-Infiltrating Cells by PD-L1 Blockade

Maekawa, Naoya; Konnai, Satoru; Ikebuchi, Ryoyo; Okagawa, Tomohiro; Adachi, Mami; Takagi, Satoshi; Kagawa, Yumiko; Nakajima, Chie; Suzuki, Yasuhiko; Shiro, Motoo; Ohashi, Kazuhiko

doi:10.1371/journal.pone.0098415

Cited by 106 publications

(150 citation statements)

References 52 publications

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“…IFN‐ γ is recognized as the principle cytokine that upregulates PD‐L1 expression on many tumour types in human and mouse models . Recently, it was reported that IFN‐ γ also upregulates PD‐L1 expression on certain canine tumour lines when used at a high concentration . We observed that all of the canine tumour cell lines evaluated in the present study upregulated PD‐L1 expression in response to IFN‐ γ in a dose‐dependent manner.…”

Section: Discussionsupporting

confidence: 66%

Immune regulation of canine tumour and macrophage PD‐L1 expression

Hartley

Faulhaber

Caldwell

et al. 2016

Vet Comparative Oncology

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Expression of programmed cell death receptor ligand 1 (PD-L1) on tumor cells has been associated with immune escape in human and murine cancers, but little is known regarding the immune regulation of PD-L1 expression by tumor cells and tumor-infiltrating macrophages in dogs. Therefore, 14 canine tumor cell lines, as well as primary cultures of canine monocytes and macrophages, were evaluated for constitutive PD-L1 expression and for responsiveness to immune stimuli. We found that PD-L1 was expressed constitutively on all canine tumor cell lines evaluated, although the levels of basal expression were very variable. Significant upregulation of PD-L1 expression by all tumor cell lines was observed following IFN-γ exposure and by exposure to a TLR3 ligand. Canine monocytes and monocyte-derived macrophages did not express PD-L1 constitutively, but did significantly upregulate expression following treatment with IFN-γ. These findings suggest that most canine tumors express PD-L1 constitutively and that both innate and adaptive immune stimuli can further upregulate PD-L1 expression. Therefore the upregulation of PD-L1 expression by tumor cells and by tumor-infiltrating macrophages in response to cytokines such as IFN-γ may represent an important mechanism of tumor-mediated T-cell suppression in dogs as well as in humans.

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Section: Discussionsupporting

confidence: 66%

Immune regulation of canine tumour and macrophage PD‐L1 expression

Hartley

Faulhaber

Caldwell

et al. 2016

Vet Comparative Oncology

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“…As a result, MHC class I (MHC I) is not expressed on the surface of DFT1 cells, but cell surface expression of MHC I can be upregulated by IFN-γ (11). One potential downside to IFN-γ stimulation is that powerful inhibitory cell surface signaling molecules, such as PD-L1, are also upregulated in response to IFN-γ signaling in a wide variety of human, mouse, and canine tumors (13–15). Indeed, the correlation between PD-L1 and IFN-γ was 100% in human melanocytic lesions (16).…”

Section: Introductionmentioning

confidence: 99%

PD-L1 Is Not Constitutively Expressed on Tasmanian Devil Facial Tumor Cells but Is Strongly Upregulated in Response to IFN-γ and Can Be Expressed in the Tumor Microenvironment

et al. 2016

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The devil facial tumor disease (DFTD) is caused by clonal transmissible cancers that have led to a catastrophic decline in the wild Tasmanian devil (Sarcophilus harrisii) population. The first transmissible tumor, now termed devil facial tumor 1 (DFT1), was first discovered in 1996 and has been continually transmitted to new hosts for at least 20 years. In 2015, a second transmissible cancer [devil facial tumor 2 (DFT2)] was discovered in wild devils, and the DFT2 is genetically distinct and independent from the DFT1. Despite the estimated 136,559 base pair substitutions and 14,647 insertions/deletions in the DFT1 genome as compared to two normal devil reference genomes, the allograft tumors are not rejected by the host immune system. Additionally, genome sequencing of two sub-strains of DFT1 detected greater than 15,000 single-base substitutions that were found in only one of the DFT1 sub-strains, demonstrating the transmissible tumors are evolving and that generation of neoantigens is likely ongoing. Recent evidence in human clinical trials suggests that blocking PD-1:PD-L1 interactions promotes antitumor immune responses and is most effective in cancers with a high number of mutations. We hypothesized that DFTD cells could exploit the PD-1:PD-L1 inhibitory pathway to evade antitumor immune responses. We developed recombinant proteins and monoclonal antibodies (mAbs) to provide the first demonstration that PD-1 binds to both PD-L1 and PD-L2 in a non-placental mammal and show that PD-L1 is upregulated in DFTD cells in response to IFN-γ. Immunohistochemistry showed that PD-L1 is rarely expressed in primary tumor masses, but low numbers of PD-L1+ non-tumor cells were detected in the microenvironment of several metastatic tumors. Importantly, in vitro testing suggests that PD-1 binding to PD-L1 and PD-L2 can be blocked by mAbs, which could be critical to understanding how the DFT allografts evade the immune system.

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“…PD‐1 is a costimulatory receptor expressed primarily on activated T cells that suppresses T‐cell activation upon binding to its ligands, PD‐ligand 1 (PD‐L1) and PD‐L2. Upregulation and aberrant expression of PD‐1 have been described in tumour antigen (TA)‐specific T cells and tumour cells, or cells within the tumour microenvironment in a variety of human cancer types, respectively . Blocking the PD‐1/PD‐L1 pathway with an anti‐PD‐1 or PD‐L1 antibody can restore multiple effector functions of antigen‐specific T cells, overcoming immune escape mechanisms by cancer cells .…”

Section: Immunotherapy Approaches For Canine Sarcomasmentioning

confidence: 99%

“…Blocking the PD‐1/PD‐L1 pathway with an anti‐PD‐1 or PD‐L1 antibody can restore multiple effector functions of antigen‐specific T cells, overcoming immune escape mechanisms by cancer cells . In dogs, PD‐1 and PD‐L1 expression have been reported in sarcomas, specifically hemangiosarcoma and osteosarcoma, but the therapeutic potential of PD‐1/PD‐L1blockade has not yet been fully elucidated . Recently, a novel rat‐dog chimeric anti‐PD‐L1 monoclonal antibody (c4G12) was tested in vitro and enhanced cytokine production and proliferation of dog peripheral mononuclear cells.…”

Section: Immunotherapy Approaches For Canine Sarcomasmentioning

confidence: 99%

Emerging therapeutic approaches for canine sarcomas: Pushing the boundaries beyond the conventional

Borgatti

Dickerson

Lawrence

2019

Vet Comparative Oncology

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Sarcomas represent a group of genomically chaotic, highly heterogenous tumours of mesenchymal origin with variable mutational load. Conventional therapy with surgery and radiation therapy is effective for managing small, low‐grade sarcomas and remains the standard therapeutic approach. For advanced, high‐grade, recurrent, or metastatic sarcomas, systemic chemotherapy provides minimal benefit, therefore, there is a drive to develop novel approaches. The discovery of “Coley's toxins” in the 19th century, and their use to stimulate the immune system supported the application of unconventional therapies for the treatment of sarcomas. While promising, this initial work was abandoned and treatment paradigm and disease course of sarcomas was largely unchanged for several decades. Exciting new therapies are currently changing treatment algorithms for advanced carcinomas and melanomas, and similar approaches are being applied to advance the field of sarcoma research. Recent discoveries in subtype‐specific cancer biology and the identification of distinct molecular targets have led to the development of promising targeted strategies with remarkable potential to change the landscape of sarcoma therapy in dogs. The purpose of this review article is to describe the current standard of care and limitations as well as emerging approaches for sarcoma therapy that span many of the most active paradigms in oncologic research, including immunotherapies, checkpoint inhibitors, and drugs capable of cellular metabolic reprogramming.

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Expression of PD-L1 on Canine Tumor Cells and Enhancement of IFN-γ Production from Tumor-Infiltrating Cells by PD-L1 Blockade

Cited by 106 publications

References 52 publications

Immune regulation of canine tumour and macrophage PD‐L1 expression

Immune regulation of canine tumour and macrophage PD‐L1 expression

PD-L1 Is Not Constitutively Expressed on Tasmanian Devil Facial Tumor Cells but Is Strongly Upregulated in Response to IFN-γ and Can Be Expressed in the Tumor Microenvironment

Emerging therapeutic approaches for canine sarcomas: Pushing the boundaries beyond the conventional

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