PD-L1 immunohistochemistry for canine cancers and clinical benefit of anti-PD-L1 antibody in dogs with pulmonary metastatic oral malignant melanoma

Maekawa, Naoya; Konnai, Satoru; Nishimura, Maki; Kagawa, Yumiko; Takagi, Satoshi; Hosoya, Kenji; Ohta, Hiroshi; Kim, Sangho; Okagawa, Tomohiro; Izumi, Yūsuke; Deguchi, Takao; Kato, Yukinari; Yamamoto, Satoshi; Yamamoto, Keiichi; Toda, Motomu; Nakajima, Chie; Suzuki, Yasuhiko; Shiro, Motoo; Ohashi, Kazuhiko

doi:10.1038/s41698-021-00147-6

Cited by 77 publications

(139 citation statements)

References 54 publications

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“…While this manuscript was in final review, Maekawa et al 20 published findings from their further studies of chimeric anti-PD-L1 monoclonal antibody therapy of canine melanoma.…”

Section: Discussionmentioning

confidence: 99%

PD-1, PD-L1, and PD-L2 Gene Expression and Tumor Infiltrating Lymphocytes in Canine Melanoma

et al. 2021

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Melanoma in humans and dogs is considered highly immunogenic; however, the function of tumor-infiltrating lymphocytes (TILs) is often suppressed in the tumor microenvironment. In humans, current immunotherapies target checkpoint molecules (such as PD-L1, expressed by tumor cells), inhibiting their suppressive effect over TILs. The role of PD-L2, an alternative PD-1 ligand also overexpressed in malignant tumors and in patients with anti-PD-L1 resistance, remains poorly understood. In the current study, we evaluated the expression of checkpoint molecule mRNAs in canine melanoma and TILs. Analysis of checkpoint molecule gene expression was performed by RT-qPCR (real-time quantitative polymerase chain reaction) using total RNA isolated from formalin-fixed and paraffin-embedded melanomas ( n = 22) and melanocytomas ( n = 9) from the Virginia Tech Animal Laboratory Services archives. Analysis of checkpoint molecule expression revealed significantly higher levels of PDCD1 ( PD-1) and CD274 ( PD-L1) mRNAs and an upward trend in PDCD1LG2 ( PD-L2) mRNA in melanomas relative to melanocytomas. Immunohistochemistry revealed markedly increased numbers of CD3+ T cells in the highest PD-1-expressing subgroup of melanomas compared to the lowest PD-1 expressors, whereas densities of IBA1+ cells (macrophages) were similar in both groups. CD79a+ cell numbers were low for both groups. As in human melanoma, overexpression of the PD-1/PD-L1/PD-L2 axis is a common feature of canine melanoma. High expression of PD-1 and PD-L1 correlates with increased numbers of CD3+ cells. Additionally, the high level of IBA1+ cells in melanomas with low PD-1 expression and low CD3+ cells levels suggest that the expression of checkpoint molecules is modulated by interactions between T cells and cancer cells rather than histiocytes.

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“…While this manuscript was in final review, Maekawa et al 20 published findings from their further studies of chimeric anti-PD-L1 monoclonal antibody therapy of canine melanoma.…”

Section: Discussionmentioning

confidence: 99%

PD-1, PD-L1, and PD-L2 Gene Expression and Tumor Infiltrating Lymphocytes in Canine Melanoma

et al. 2021

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“…Since T cells were located at the periphery of canine HSA cases, macrophages in canine HSA likely facilitate immune evasion by through induction of PD-L1 expression. Antibodies specific for canine PD-L1 have been developed and have been tested for their safety and efficacy in clinical cases 20–22 . However, anti-PD-L1 antibody treatment has not been studied in canine HSA patients.…”

Section: Discussionmentioning

confidence: 99%

Hemangiosarcoma cells induce M2 polarization and PD-L1 expression in macrophages

Gulay

Aoshima

Maekawa

et al. 2021

Preprint

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Hemangiosarcoma (HSA) is a malignant tumor derived from endothelial cells. Tumor-associated macrophages are one of the major components of tumor microenvironment and crucial for cancer development. The presence and function of macrophages in HSA have not been studied because there is no syngeneic model for HSA. In this study, we evaluated two mouse HSA cell lines and one immortalized mouse endothelial cells for their usefulness as syngeneic models for canine HSA. Our results show that the ISOS-1 cell line develops tumors with similar morphology to canine HSA. ISOS-1 cells highly express KDM2B and have similar KDM2B target expression patterns with canine HSA. Moreover, we determine that in both ISOS-1 and canine HSA tumors, macrophages are present as a major constituent of the tumor microenvironment. These macrophages are positive for CD204, an M2 macrophage marker, and express PD-L1. ISOS-1-conditioned medium can induce M2 polarization and PD-L1 expression in RAW264.7 mouse macrophage cell line. These results show that ISOS-1 can be used as a syngenic model for canine HSA and suggest that macrophages play an important role in immune evasion in HSA. Using the syngeneic mouse model for canine HSA, we can further study the role of immune cells in the pathology of HSA.

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“…IFN-γ has also been shown to enhance PD-L1 expression in canine tumor cell lines [86,91,93]. However, only our group [94] and Maekawa et al [95,96] have reported clinical trials using these antibody drugs in cancer-bearing dogs. The first clinical trial for this indication was conducted by the Hokkaido University group.…”

Section: Next Generations Of Immunotherapy In Dogsmentioning

confidence: 97%

“…In their pilot report [95], partial remission was observed in one of seven canine OMM cases and one of two undifferentiated sarcoma cases treated with anti-dog PD-L1 chimeric antibodies. Recently, they reported on a clinical trial wherein antibodies were administered to 30 dogs with stage IV OMM [96]. They found complete remission in 1 of 13 dogs that had 'measurable diseases' at baseline, and the resolution of lung metastases in 4 of 17 dogs with lung metastases that were classified as 'non-measurable lesions' at baseline, according to the canine response evaluation criteria for solid tumors (RECIST) v1.0.…”

Section: Next Generations Of Immunotherapy In Dogsmentioning

confidence: 99%

Spontaneously occurring canine cancer as a relevant animal model for developing novel treatments for human cancers

Mizuno

2021

Translational and Regulatory Sciences

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The most common cause of death among adult or older dogs is malignancy. Dogs spontaneously develop malignant tumors with age, and the incidence of malignant tumors in dogs is higher than that in humans. Basic research on treatment of tumors is generally conducted using syngeneic or immunodeficient mice, which have some shortcomings as a model for human tumors that develop over a long period of time, while interacting with the host immune system. On the other hand, naturally occurring canine tumors develop under immunocompetent conditions and may be suitable for preclinical studies, especially for the development of therapies that affect host immunity. In this review, some of the canine tumors and immunotherapies that have been implemented thus far will be discussed, with the intent of helping establish cancer treatment research, using dogs with naturally occurring tumors, for translational studies in humans.

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PD-L1 immunohistochemistry for canine cancers and clinical benefit of anti-PD-L1 antibody in dogs with pulmonary metastatic oral malignant melanoma

Cited by 77 publications

References 54 publications

PD-1, PD-L1, and PD-L2 Gene Expression and Tumor Infiltrating Lymphocytes in Canine Melanoma

PD-1, PD-L1, and PD-L2 Gene Expression and Tumor Infiltrating Lymphocytes in Canine Melanoma

Hemangiosarcoma cells induce M2 polarization and PD-L1 expression in macrophages

Spontaneously occurring canine cancer as a relevant animal model for developing novel treatments for human cancers

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