Feline mammary carcinomas are associated with an immunosuppressed vascularized and proliferative microenvironment

Due to their aggressive presentation, feline mammary carcinomas (FMC) often have deadly consequences. The tumor immune microenvironment (TIME) has a presumed critical role in the natural host defense against FMC development, but remains underinvestigated. To characterize the FMC TIME, 8 low grade and 21 high grade FMC were retrospectively collected. Immunohistochemical analysis of a set of complementary innate and adaptive immune cell markers, together with the von Willebrand factor (vWF)+ blood vessel density, the Ki67-based proliferation index and the hormonal receptor status allowed us to both spatially and quantitatively investigate the FMC TIME across tumor grades. Overall, higher abundancies of immune cells and more prominent vascularization were detected in high compared to low grade FMC. In contrast, a similar proliferation index was measured across FMC grades. Innate immune cells, i.e., HLA-DR+ antigen-presenting cells, CD163+ tumor-associated immunosuppressive macrophages and MPO+ tumor-associated neutrophils, mainly resided in the tumoral stroma forming an immunosuppressive border surrounding the tumor core. CD3+ T lymphocytes were able to populate the tumoral core, whereas CD20+ B lymphocytes clustered together, assumably in tertiary lymphoid structures, in the tumoral stroma. Unexpectedly, both low and high grade FMC were associated with the luminal (A and B) subtypes, mainly due to their progesterone receptor positivity. Collectively, our data identify that FMC are associated with an immunosuppressed, vascularized and proliferative TIME, which should be further explored for its (immune)therapeutic potential including that of anti-progestins.