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. Here we found that 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 the 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.

Tumor-Infiltrating Lymphocytes (TILs) in Epithelial Ovarian Cancer: Heterogeneity, Prognostic Impact, and Relationship with Immune Checkpoints

“…CD3-staining iTILs based on the TILs count are counted either manually or using digital imaging analysis to determine the number of T cells per HPF (ranging from 15 to 20 HPF). Several studies found a positive effect of CD3+ TILs [ 44 , 63 , 76 , 77 , 78 , 79 ], and one showed no impact on the prognosis [ 80 ]. The CD3 location can modify the prognosis: sCD3+ TILs are associated with an improved 10-year survival rate [ 81 ], whereas iCD3+ TILs have no impact on OS or DFS [ 82 ].…”

“…When only intraepithelial CD8 cells are studied, the results are more heterogeneous, with one study having a positive effect on OS [ 24 ], two studies having a positive effect on DFS [ 87 , 93 ], three studies without a significant impact [ 39 , 94 , 95 ], and three studies having a negative effect on survival [ 82 , 96 , 97 ]. The results for TREG also vary, with either studies showing a negative impact on OS and DFS [ 45 , 78 , 90 , 94 ], or finding no impact or [ 49 , 79 , 82 ] even a positive impact [ 45 , 98 ].…”

NANOG regulates epithelial–mesenchymal transition via AMPK/mTOR signalling pathway in ovarian cancer SKOV‐3 and A2780 cells

“…TMA, which was constructed in previous studies, was used in this study. 27 , 28 The TMA blocks were cut to 5‐μm thickness with a rotary microtome. After sectioning, the TMA sections were deparaffinized with xylene and dehydrated in serially graded ethanol to distilled water.…”

“…TMA, which was constructed in previous studies, was used in this study 27,28 . The TMA blocks were cut to 5‐μm thickness with a rotary microtome.…”

Etiopathogenesis of ovarian cancer. An inflamm-aging entity?

“…The gonadotropin stimulation hypothesis proposes that high gonadotropin levels can influence OSE cells and promote carcinogenesis ( Mertens-Walker et al, 2012 ) by increasing the proliferation and mitotic activity of the ovarian epithelium ( Han et al, 2021 ). This fact could explain why the majority of patients present with OvCa after menopause ( American Cancer Society ).…”