Immunohistochemical Analysis of PD-L1 Expression in Canine Malignant Cancers and PD-1 Expression on Lymphocytes in Canine Oral Melanoma

Abstract

Spontaneous cancers are common diseases in dogs. Among these, some malignant cancers such as oral melanoma, osteosarcoma, hemangiosarcoma, and mast cell tumor are often recognized as clinical problems because, despite their high frequencies, current treatments for these cancers may not always achieve satisfying outcomes. The absence of effective systemic therapies against these cancers leads researchers to investigate novel therapeutic modalities, including immunotherapy. Programmed death 1 (PD-1) is a costimulatory receptor with immunosuppressive function. When it binds its ligands, PD-ligand 1 (PD-L1) or PD-L2, PD-1 on T cells negatively regulates activating signals from the T cell receptor, resulting in the inhibition of the effector function of cytotoxic T lymphocytes. Aberrant PD-L1 expression has been reported in many human cancers and is considered an immune escape mechanism for cancers. In clinical trials, anti-PD-1 or anti-PD-L1 antibodies induced tumor regression for several malignancies, including advanced melanoma, non-small cell lung carcinoma, and renal cell carcinoma. In this study, to assess the potential of the PD-1/PD-L1 axis as a novel therapeutic target for canine cancer immunotherapy, immunohistochemical analysis of PD-L1 expression in various malignant cancers of dogs was performed. Here, we show that dog oral melanoma, osteosarcoma, hemangiosarcoma, mast cell tumor, mammary adenocarcinoma, and prostate adenocarcinoma expressed PD-L1, whereas some other types of cancer did not. In addition, PD-1 was highly expressed on tumor-infiltrating lymphocytes obtained from oral melanoma, showing that lymphocytes in this cancer type might have been functionally exhausted. These results strongly encourage the clinical application of PD-1/PD-L1 inhibitors as novel therapeutic agents against these cancers in dogs.

The contribution of immune infiltrates and the local microenvironment in the pathogenesis of osteosarcoma

“…Similarly, osteosarcoma cells express B7-H3 which is correlated with the aggressiveness of the disease and metastatic capacity [85,86]. Program Death Ligand-1 (PDL-1) and PDL-2 were also detectable in all osteosarcoma cases [89][90][91][92][93][94].…”

PD‐1 expression by canine T cells and functional effects of PD‐1 blockade

“…It was also proposed that FIV infected cats could serve as a model for investigating the effects of PD‐1 blockade on control of chronic lentiviral infection . Recently it has been reported by our group and others that PD‐L1 is expressed on canine tumour cells and macrophages, both in vitro and in vivo . In dogs with visceral leishmaniasis, it was reported recently that PD‐1 signalling could induce T cell apoptosis …”

Podoplanin Expression in Canine Melanoma

“…(20) We stained 10 canine oral melanomas, which are the most frequent oral cancers in dog. (22) As depicted in Figures 1 and 2A, melanoma cells were stained by PMab-38 in 9 of 10 cases. Although melanoma cells were not stained by PMab-38 in case 9 ( Fig.…”