PD-L2 reverse signaling suppresses tumor cell proliferation and serves as a prognostic indicator in canine high-grade mast cell tumors

Daichi Hanai, Ryusei Kimura, Ikki Mitsui, Jiro Miyamae, Akira Matsuda, Hiroaki Hemmi, Kohei Murakami

Mast cell tumors (MCTs) are common skin neoplasms in dogs. They are graded histologically, and dogs with high-grade MCT have poorer prognosis. Canine MCTs express mRNA for programmed cell death-1 ligand 2 (PD-L2), which regulates T cell activity and serves as a prognostic indicator for various human tumors. We hypothesized that PD-L2 contributes to immune evasion and affects the prognosis of canine MCTs. PD-L2 expression was evaluated by immunohistochemistry in 38 canine MCTs, including 15 Kiupel low-grade and 23 high-grade cases. PD-L2 was primarily detected on tumor cell surfaces, and most cells in low-grade MCTs (median percentage of PD-L2-positive tumor cells: 83.5%) expressed PD-L2. In contrast, PD-L2 expression was highly variable in high-grade MCTs (median: 25.5%), and cases with fewer PD-L2-positive tumor cells had poorer prognosis than those with more (median survival time: 148 vs. 468 days). This unexpected result led us to examine the novel hypothesis that PD-L2 on tumor cells negatively regulates behavior of tumor cells by receiving reverse signals. Consistent with this, RNA-sequencing detected altered expression of 70 genes, following adenovirus-mediated PD-L2 gene transfer in the canine MCT cell line BR and subsequent soluble PD-1 exposure. Moreover, PD-1-PD-L2 reverse signaling suppressed cell proliferation in PD-L2-expressing BR cells. Collectively, our findings demonstrate the prognostic significance of PD-L2 expression in dogs with high-grade MCTs and suggest that cell proliferation of PD-L2-positive tumor cells may be regulated by PD-L2 reverse signaling.

The Veterinary Journal

317

106710

10.1016/j.tvjl.2026.106710.

https://www.sciencedirect.com/science/article/pii/S1090023326001668?via%3Dihub