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

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 cell line for their usefulness as syngeneic models for canine HSA. Our results showed that the ISOS-1 cell line developed tumors with similar morphology to canine HSA. ISOS-1 cells highly expressed KDM2B and had similar KDM2B target expression patterns with canine HSA. Moreover, we determined that in both ISOS-1 and canine HSA tumors, macrophages were present as a major constituent of the tumor microenvironment. These macrophages were positive for CD204, an M2 macrophage marker, and express PD-L1, an immune checkpoint molecule. Canine HSA with macrophages expressing PD-L1 had a smaller number of T-cells in tumor tissues than tumors with PD-L1 negative macrophages. ISOS-1-conditioned medium could induce M2 polarization and PD-L1 expression in RAW264.7 mouse macrophage cell line and mouse peritoneal macrophages. 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.

The expression of histone lysine demethylase 2B in canine hemangiosarcoma is associated with disease progression.

Canine hemangiosarcoma (HSA), a highly fatal mesenchymal tumour of dogs, originates from the endothelial cells lining of blood vessels. It is characterized by a short survival time with a mean survival time of only 4 months. Recently, we showed that histone lysine demethylase 2B (KDM2B) was highly expressed in canine HSA and was important in HSA tumour cell survival by positively regulating DNA repair mechanisms. KDM2B has been reported to be related to disease progression and patient survival in several human cancers. Thus, in this study, we studied the relationship of KDM2B expression levels with several patient clinical profiles to investigate the role of KDM2B in clinical HSA tumours. We analysed 37 canine HSA cases and found that KDM2B is highly expressed in stage 3 HSA compared to stage 1 HSA. High KDM2B expression was also found in male dogs compared to female dogs. No correlation was observed between KDM2B expression and age. Classifying HSA patients into high and low KDM2B expression groups revealed that the high KDM2B group showed shorter overall survival than the low KDM2B group. Based on these results, we suggest that KDM2B expression is associated with disease progression in HSA.