Characterization of Estrogen Receptors in Pancreatic Adenocarcinoma with Tertiary Lymphoid Structures

SIMPLE SUMMARY: The role of estrogen signaling in pancreatic adenocarcinoma (PAAD) was unclear. Here we investigated the expression patterns of three estrogen receptors (ERα, ERβ, and GPER) in 174 PAAD samples via immunohistochemistry staining. Positive expression of all three estrogen receptors was significantly correlated with better clinicopathological characteristics and prognosis, as well as more tertiary lymphoid structure (TLS) presence in PAAD. Upregulated expression of ERα and ERβ in PAAD was also significantly associated with increased CD8(+) T-cell infiltration in vitro. In-silico analyses also revealed that the expression of estrogen receptors affects multiple pathways relevant to T-cell and B-cell behaviors. In summary, estrogen receptors may remodel the immune microenvironment and regulate the development of TLS in PAAD. ABSTRACT: The role of estrogen signaling in antitumor immunology remains unknown for non-traditional sex-biased cancer types such as pancreatic adenocarcinoma (PAAD). Tertiary lymphoid structures (TLS) are active zones composed of multiple types of immune cells, whose presence indicates anti-tumor immune responses. In this study, we employed a 12-chemokine signature to characterize potential gene categories associated with TLS development and identified seventeen major gene categories including estrogen receptors (ERs). Immunohistochemistry staining revealed the expression patterns of three ERs (ERα, ERβ, and GPER) in 174 PAAD samples, and their correlation with clinicopathological characteristics, immune cell infiltration levels, and intratumoral TLS presence was analyzed. The results indicated that ERα (+) and ERβ (+) were correlated with high tumor grade, and ERβ (+) and GPER (+) were correlated with lower TNM stage, and both ERα (+) and GPER (+) displayed a beneficial effect on prognosis in this cohort. Interestingly, positive staining of all three ERs was significantly correlated with the presence of intratumoral TLSs and infiltration of more active immune cells into the microenvironment. Moreover, the chemotaxis of CD8(+)T-cells to PAAD cells was significantly increased in vitro with upregulated expression of ERα or ERβ on PAAD cells. To conclude, our study showed a novel correlation between ER expression and TLS development, suggesting that ERs may play a protective role by enhancing anti-tumor immune responses in PAAD.