Studying the Effect of β-estradiol on HCC Antigen-Specific T Cells

Abstract

Abstract Hepatocellular carcinoma (HCC) has a 4:1 male-to-female overall incidence ratio. These statistics lead to the belief that there are gender specific mechanisms that affect the development of this cancer. Previous research studies demonstrated that the gender differences regarding HCC may be related to a protective effect from estrogen (E2). However, the antitumor immune response following cancer development is not defined. To test specific immune responses to HCC we are utilizing a known hepatitis C virus (HCV) antigen to generate Ag-specific T cells that target HCC expressing the HCV antigen since the chronic infection of accounts for approximately 50% of HCC. With this model, we tested the effect of E2 on the immune response during immunotherapy. We have identified a novel effect of E2 treatment of TCR-transduced Ag-specific T cells. E2 treatment induced an increase in their cytotoxicity and effector function. Treatment at super physiological concentrations of β-estradiol resulted in an up-regulation of CD107a expression, demonstrating degranulation and an increase in TNFα secretion. On the other hand, E2 treatment also caused a reduction in the number of cytokines produced simultaneously demonstrated in a polyfunctional analysis of the T cells. Polycytokine profiles of the T cells showed that as E2 increases, the number of T cells producing 3 or 4 cytokines simultaneously decreases while the number of T cells displaying a reduced number of functions increases. Previous studies on memory T cell development show that memory T cells result from cells with greater polyfunctional abilities. Our results suggest that while exposure to E2 increases rapid effector function, it is at the expense of the generation of memory T cells.