Abstract
Crosstalk between neoplastic and immune cells in the tumor microenvironment (TME) influences the progression of disease in human and canine cancer patients. Given that canine mammary tumors are a useful model to study breast cancer biology, we aimed to evaluate the expression of genes associated with T lymphocyte activity in benign, malignant, and metastatic canine mammary tumors. Interestingly, metastatic tumors exhibit increased expression of CXCR3, CCR2, IL-4, IL-12p40, and IL-17. In particular, we focused on IL-17, a key interleukin associated with the Th17 lymphocyte phenotype. Th17 cells have been shown to play a contradictory role in tumor immunity. Although IL-17 showed a high expression in the metastatic tumors, the expression of RORγt, a crucial transcription factor for Th17 differentiation was barely detected. We further investigated IL-17 expression using immunohistochemistry, through which we confirmed the increased expression of this interleukin in malignant and metastatic mammary tumors. Finally, we compared the plasma levels of IL-17 in healthy and malignant mammary tumor-bearing dogs using ELISA but found no differences between the groups. Our data indicate that the IL-17 in metastatic tumors may be produced by other cell types, but not by Th17 lymphocytes. Overall, our results broaden the available knowledge on the interactions in canine mammary tumors and provide insight into the development of new therapeutic strategies, with potential benefits for human immune oncology.
Highlights
Mammary gland tumors are one of the most common cancers in dogs, especially in non-spayed females, and are still one of the leading causes of death among canines [1,2,3]
Since T regulatory (Treg) infiltration has already been extensively studied in mammary canine tumors [28,29], we focused on the expression of other T lymphocyte-associated factors in canine mammary tumors
We found that the expression of both PD-L2 and Gal9 genes was highly upregulated in the malignant mammary tumors compared to the healthy tissue
Summary
Mammary gland tumors are one of the most common cancers in dogs, especially in non-spayed females, and are still one of the leading causes of death among canines [1,2,3]. Significant analogies at the molecular level have been shown in genome-wide comparative studies of mammary cancers between human and canine. It is currently well recognized that a tumor mass is composed of transformed cancer cells and of stroma cells (fibroblasts, mesenchymal stem cells, adipocytes, blood, and lymphatic endothelial cells) and inflammatory cells (macrophages, neutrophils, dendritic cells, T lymphocytes, and NK cells). These elements, together with signaling molecules, create the tumor microenvironment (TME) in humans as well as in dogs [6,7,8]. Emerging evidence indicates highly conserved stromal reprogramming between canine and human mammary carcinoma, which supports the validity of using spontaneous canine mammary tumors as a model for human disease [7,11,12]
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