4.4 Article

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

Journal

VETERINARY PATHOLOGY
Volume 58, Issue 4, Pages 692-698

Publisher

SAGE PUBLICATIONS INC
DOI: 10.1177/03009858211011939

Keywords

dog melanoma; tumor infiltrating lymphocytes; B7-H1 antigen; CD274 protein; CD273 protein; PD-1; PD-L1; PD-L2

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In both canine and human melanoma, overexpression of the PD-1/PD-L1/PD-L2 axis is a common feature. High levels of PD-1 and PD-L1 are associated with increased numbers of CD3(+) cells.
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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