The stromal tumor-infiltrating lymphocytes, cancer stemness, epithelial-mesenchymal transition, and B7-H4 expression in ovarian serous carcinoma

Background: B7-H4 is expressed in various types of cancers and its expression inversely correlates with the degree of tumor-infiltrating lymphocytes (TILs). Studies have shown the relationship between B7-H4, cancer stem cell (CSC) properties, and epithelial-mesenchymal transition (EMT) in various cancers. However, very few studies have investigated the relationship between B7-H4, TILs, cancer stemness, and EMT in epithelial ovarian cancer (EOC). The present study aimed to elucidate whether B7-H4 is involved in immune evasion and examine whether B7-H4 is associated with cancer stemness or EMT in ovarian serous carcinoma, the most common type of EOC. The clinical significance of B7-H4 was also investigated to evaluate its potential as a therapeutic target. Methods: A total of 145 patients included in this study. The degree of stromal TILs was evaluated using hematoxylin and eosin (H&E)-stained slides. Immunohistochemical analysis of B7-H4, CSC-related biomarkers (CD24, CD44s, CD133, and ALDH1), and EMT-related biomarkers (E-cadherin, N-cadherin, and vimentin) was performed using tissue microarray. qRT-PCR for VTCN1 , CD24 , CD44 , PROM1 , ALDH1 , CDH1 , CDH2 , and VIM genes was performed on 38 frozen tissue samples. The mRNA expression levels were analyzed using Gene Expression Profiling Interactive Analysis (GEPIA) online analysis tool. Results: B7-H4 protein expression positively correlated with the degree of stromal TILs. CD24, CD44s, and CD133 expression showed a positive correlation with B7-H4 expression at both the protein and mRNA levels, but ALDH1 correlated only at the protein level. E-cadherin expression was positively correlated with B7-H4 expression at both the protein and mRNA levels. N-cadherin and vimentin expression was inversely related to B7-H4 expression only at the mRNA level. B7-H4 positive patients were associated with higher tumor grade and lower overall survival rate than B7-H4 negative patients, especially in ovarian serous carcinoma with low stromal TILs. Conclusions: The present study demonstrates that B7-H4 may not be involved in the immune evasion mechanism, but is involved in cancer stemness and mesenchymal-epithelial transition. In addition, B7-H4 may be a therapeutic target for the treatment of ovarian serous carcinoma, especially with low stromal TILs.