Clinical significance of tumor infiltrating lymphocytes in association with hormone receptor expression patterns in epithelial ovarian cancer

Abstract

Hormone receptor expression patterns often correlate with infiltration of specific lymphocytes in tumors. Specifically, the presence of specific tumor infiltrating lymphocytes (TILs) with particular hormone receptor expression is reportedly associated with breast cancer, however, this has not been revealed in epithelial ovarian cancer (EOC). Therefore, we investigated the association between hormone receptor expression and TILs in EOC. Immunohistochemical analysis of estrogen receptor (ER)α, androgen receptor (AR), glucocorticoid receptor (GR), progesterone receptor (PR), ERβ, CD3+, CD4+, CD8+, FoxP3+, PD-1, and PD-L1 was performed using tissue microarray analysis or whole sections. NanoString analyses compared normal epithelial and EOC tissues, which were clustered based on hormone receptor expression patterns using complementary bioinformatic approaches. ERα, AR, and GR expression increased in EOC, while PR was significantly reduced and ERβ expression showed a reduced trend compared to normal epithelium. Cluster analysis indicated poor disease free survival (DFS) in AR+/GR+/PR+ subgroup (triple dominant group); while Cox proportional-hazards model highlighted the triple dominant group as an independent prognostic factor for DFS. In addition, significant upregulation of FoxP3+ TILs, PD-1, and PD-L1 was observed in the triple dominant group compared to other groups. NanoString analyses further suggested that tumor necrosis factor (TNF) and/or NF-κB signaling pathways were activated with significant upregulation of RELA, MAP3K5, TNFAIP3, BCL2L1, RIPK1, TRAF2, PARP1, and AKT1 in the triple dominant EOC group. The triple dominant subgroup correlates with poor prognosis in EOC. Moreover, the TNF and/or NF-κB signaling pathways may be responsible for hormone-mediated inhibition of the immune microenvironment.