Increased co-expression of stromal HHLA2 and fibroblast activation protein in upper tract urothelial carcinoma

BACKGROUND: The human endogenous retrovirus-H long terminal repeat-associating protein 2 (HHLA2; also known as B7 homolog 7 [B7-H7]) regulates immune responses. However, its immunoregulatory role in upper tract urothelial carcinoma (UTUC) remains unclear. METHODS: We evaluated the immunohistochemical expression of HHLA2 and fibroblast activation protein (FAP), which is a marker of cancer-associated fibroblasts, in UTUC tissues from 85 patients who underwent nephroureterectomy. The associations between the expressions of HHLA2 and FAP and clinicopathological characteristics were investigated. RESULTS: The increased expression of HHLA2 in tumor cells (t-HHLA2) was associated with a low histological grade, a negative lymphovascular invasion (LVI), and a low neutrophil-to-lymphocyte ratio, whereas an increased expression of HHLA2 in stromal cells (s-HHLA2) was associated with a high histological grade. No correlation was observed between the expression of t-HHLA2 and s-HHLA2. FAP was expressed only in the stromal cells (s-FAP). Positive s-FAP expression was significantly associated with increased s-HHLA2 expression, higher histological grade, higher pathological T stage, and positive LVI. Higher t-HHLA2 was associated with longer cancer-specific and progression-free survival. In contrast, positive s-FAP was associated with short progression-free survival. CONCLUSION: These findings suggest that the progression of UTUC may involve increased co-expression of HHLA2 and FAP in the tumor stroma.