Abstract
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.
Highlights
Hemangiosarcoma (HSA) is a malignant tumor derived from endothelial cells
In single layer culture, both the mouse and canine HSA cell lines are characterized by spindle to polygonal cells with a moderate amount of cytoplasm and elongated nuclei arranged in cobblestone pattern (Fig. S1)
We stained ISOS-1 tumors and canine HSA cases with anti-CD204 antibody and identified a large number of CD204 positive cells in ISOS-1 tumors and canine HSA samples (Fig. 2G). These results suggest that HSA tumor cells can recruit macrophages into the tumor microenvironment and polarize them to M2 macrophages
Summary
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. 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. ISOS-1 was established from a tumor formed by the xenotransplantation of a human angiosarcoma cell line, while UV♀2 cell line was developed from an ultraviolet light-induced angioendothelioma-like tumor[9,10] Their usefulness as syngeneic models for canine HSA or human angiosarcoma, has not yet been evaluated. It is highly likely that M2 macrophages support tumor development and facilitate immune evasion in HSA; there are no studies that have evaluated their presence and functions in HSA
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