Estrogen Mediates Sex Related Differences in T cell Function and Anti-Tumor Immunity
Flor C. Navarro, Stephanie K. Watkins Ph.D.
Loyola University Chicago
The gender difference in cancer susceptibility, and survival is one of the most consistent findings in cancer epidemiology. It has been reported that men are 16% more likely to get cancer, and 40% more likely to die from it than women. A clear example of this can be observed in hepatocellular carcinoma (HCC), which has a 4:1 male-to-female overall incidence ratio. This gender bias can be attributed to the female sex hormone since the HCC incidence markedly increases in postmenopausal women that do not undergo hormone replacement therapy (HRT). The effects of estrogen in the tumor cells has been previously studied however, the antitumor immune response following cancer in female versus male has not been defined. Gender specific differences are also observed in non-malignant disease such as autoimmunity. Females are generally more frequently affected than males, and this is attributed to the effects of estrogen on immune cells. Knowing all this, we hypothesize that the sex hormones have different effects on the tumor immune response. Since estrogen has been reported to have an activating effect in immune cells, we want to determine if the protective effect of estrogen in cancer is due to its effects on the tumor immune response. To test the effect of estrogen on anti-tumor immunity we are utilizing two known and relevant antigens (HCV, and tyrosinase) to generate antigen specific T cells that target HCC expressing the HCV antigen, and tyrosinase-expressing melanoma cells respectively. We have identified a novel effect of 17β-estradiol treatment on TcR-transduced antigen specific T cells. Estrogen treatment rapidly induced an increase in cytotoxicity and effector function of female T cells (increase in IFNγ, and GzmB production). Treatment at super physiological concentrations of β-estradiol resulted in an up-regulation of CD107a, and TNFα secretion. On the other hand, estrogen treatment also caused a reduction in the number of cytokines produced simultaneously demonstrated in a polyfunctional analysis of the T cells. The polycytokine profiles of the Ag-specific T cells show that as the concentration of estrogen 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. Interestingly, taken together with previous studies on memory T cell development that show that memory T cells result from cells with greater polyfunctional abilities; these results suggest that while exposure to estrogen increases rapid effector function, these functions result at the expense of the generation of memory T cells. The effects of estrogen on male T cells were shown to be different. Treatment at super physiological concentrations of β-estradiol resulted in an increase on TNFα, and IL-4 expression while CD107a was not increased. This corresponds with a non-lytic more T helper cell phenotype. Further research is in progress that will reveal the mechanism through which estrogen acts on Ag-specific T cells. Also, future directions include researching the effect of androgens in the anti-tumor response as well. The overall goal of this research is to better understand sex differences in T cell anti-tumor immunity so they can ultimately be used in immunotherapy to generate a lasting anti-tumor immune response against HCC, and other malignancies.
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