VISTA Is a Diagnostic Biomarker and Immunotherapy Target of Aggressive Feline Mammary Carcinoma Subtypes

SIMPLE SUMMARY: Mammary tumors are common in cats, showing aggressive behavior and few therapeutic options. Recently, feline mammary carcinomas have become a reliable cancer model for human breast cancer studies, due to the similarities between the two species. Thus, the identification of new tumor biomarkers and therapeutic targets to improve cat’s prognosis is needed. VISTA is an important immune checkpoint protein that has gained importance over the past few years in women’s cancers. In this study, the serum VISTA levels and tumor expression were analyzed in cats with mammary tumors, being correlated with other immune checkpoints. In the diseased animals, VISTA is overexpressed in more aggressive tumor subtypes (HER2-positive and triple-negative), showing a positive correlation with the expression of VISTA in tumor-infiltrating lymphocytes, and is associated with an immunosuppressive status, suggesting that VISTA could be a promising non-invasive prognostic biomarker and therapeutic target in cats with mammary carcinomas, as reported in humans. ABSTRACT: Feline mammary carcinoma (FMC) is a common neoplasia, showing aggressive clinicopathological features, without viable therapeutic options. The study of tumor microenvironment has gained importance, due to the ability to control tumor progression by regulating the immune response. Considering the lack of knowledge, feline serum VISTA levels from cats with mammary carcinoma were compared with healthy controls, and with serum levels of PD-1/PD-L1, CTLA-4, LAG-3, IL-6, and TNF-α. In parallel, VISTA tumor expression was evaluated in FMC samples. The obtained data revealed that serum VISTA levels were significantly higher in cats presenting HER2-positive (p = 0.0025) or triple-negative subtypes (p = 0.0019), with higher serum levels in luminal A (p = 0.0025) correlated to the presence of metastasis (p = 0.0471). Furthermore, in HER2-positive or triple-negative tumors, correlations were obtained between serum VISTA levels and the serum levels of the above-mentioned molecules. In tumors, VISTA expression revealed a stronger intensity in cancer cells, when compared to TILs (p < 0.0001). Stratifying the samples by subtypes, a higher number of VISTA-positive TILs was observed in the HER2-positive subtype, compared with triple-negative tumors (p = 0.0138). In conclusion, results support the development of therapeutic strategies for HER2-positive and triple-negative FMC subtypes, reinforcing the use of cats as a human oncology model.