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

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.

Manipulating histone acetylation leads to antitumor effects in hemangiosarcoma cells

“…However, other upregulated genes in our study, CXCL8 and CXCL12, have been reported to promote tumour progression by several mechanisms such as inducing angiogenesis or polarizing macrophages to an M2 state. [59][60][61] Furthermore, given that a recent report demonstrated that a large numbers of M2-polarized macrophages exist in HSA tumour tissues and HSA cells could induce M2 polarization in macrophages, 32 HDACi might promote HSA tumour progression by upregulating the expression of tumour-promoting cytokines such as CXCL8 and CXCL12. Further research is required to understand the effects of HDACi on tumour immunity in HSA.…”

“…Given that tumour cells dynamically interact with immune cells in tumour tissues, investigating tumour pathogenesis in immunocompetent environments is crucial to develop new therapeutics such as immunotherapy and metabolic therapy 28–30 . We recently identified that a mouse‐derived AS cell line ISOS‐1, which is transplantable in Balb/c mice, has similar morphological and molecular characteristics to canine HSA cell lines 31,32 . Identifying pathological similarities between canine HSA cell‐derived tumours and murine AS cell‐derived tumours in mice would be beneficial to find novel therapeutics involving the host immune system by promoting syngeneic mouse model studies in HSA.…”

“…[28][29][30] We recently identified that a mouse-derived AS cell line ISOS-1, which is transplantable in Balb/c mice, has similar morphological and molecular characteristics to canine HSA cell lines. 31,32 Identifying pathological similarities between canine HSA cell-derived tumours and murine AS cell-derived tumours in mice would be beneficial to find novel therapeutics involving the host immune system by promoting syngeneic mouse model studies in HSA.…”

Tumor-associated macrophages: Prognostic and therapeutic targets for cancer in humans and dogs

“…These tumors with PD-L1-expressing M2 macrophages had lower numbers of T cells in the TME. Additionally, M2 polarization and PD-L1 expression could be induced by tumor-conditioned media ( 167 ). In samples of canine tumors, pulmonary metastases from hemangiosarcoma were shown to have greater numbers of monocytes compared to metastases from other tumor types, as well as significantly higher CCL2 production, a monocyte chemoattractant protein (also called MCP-1) ( 174 ).…”

New molecular targets in canine hemangiosarcoma—Comparative review and future of the precision medicine

“…235 As proven in laboratory conditions, it might be a potentially targetable aberration due to the fact that GSK-J4, a histone demethylase inhibitor, induces apoptosis leading to cell death and also decreases tumour size. 234 In mouse derived HSA cells, Gulay et al 235 proved that macrophages are major constituents of the tumour microenvironment, 236 and HSA cells can independently induce M2 polarization and PD-L1 expression on them.…”