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.

Automated summary

This study investigated the expression of HHLA2 and FAP in UTUC tissues and found that increased expression of HHLA2 in tumor cells was associated with a favorable clinical profile, while increased expression of HHLA2 in stromal cells was associated with a higher histological grade. Furthermore, positive expression of FAP in stromal cells was significantly associated with higher histological grade, advanced disease stage, and lymphovascular invasion. Higher expression of t-HHLA2 was associated with better survival outcomes, while positive expression of s-FAP was associated with shorter progression-free survival.