Estrogen Stimulation Differentially Impacts Human Male and Female Antigen-Specific T Cell Anti-Tumor Function and Polyfunctionality

Abstract

Sex-specific differences exist in innate and adaptive immune responses and are mediated by hormone signaling. Estrogen is able to differentially modulate the development and differentiation of immune cells, including T cells. However, the effect of estrogen on T cell function, especially at concentrations other than physiological, remains controversial and incompletely understood. Immunotherapy is one of the most promising cancer treatments to date with a high probability of future enhancements. The adoptive transfer of genetically modified T cells can mediate tumor regression but there are still many hurdles to enhancing the proficiency of this treatment. This study demonstrates for the first time that one major aspect to consider for designing potent immunotherapies for cancer is the impact of the patient's sex. Herein, using two different Ag-specific T cell groups, we investigated the effect of sex and estrogen in antitumor effector responses, T helper cytokine secretion, and, importantly, on T cell whole polyfunctionality important for memory T cell development and survival. Major differences were observed in T cell function and polyfunctionality between sexes and on E2 treatment. The findings of this study may be critical to understand the results of immunotherapy on different patients and for the enhancement of immunotherapy for cancer.

Estrogen Regulation of T-Cell Function and Its Impact on the Tumor Microenvironment

“…This was due to male donor T-cell populations having a higher ratio of CD8:CD4 T cells compared to female donors. 100 This supported the conclusion that estrogen modulates differentiation of human single positive CD4/CD8 T cells, which is the reason that males and females show different ratios of T-cell subsets worldwide. 101 Furthermore, the same study also reported that estrogen treatment increased TNFa and IL-4 secretion on CD8 þ T cells of both males and females.…”

“…101 Furthermore, the same study also reported that estrogen treatment increased TNFa and IL-4 secretion on CD8 þ T cells of both males and females. 100 The positive estrogen effect on IL-4 expression was shown to be completely dependent on ERa because once T cells were treated with estrogen in combination with MPP-dihydrochloride, which is a complete blockade of the ERa, IL-4 secretion was lowered to the level of unstimulated T cells in both males and females. 100 On the other hand, selectively blocking ERb had no effect on IL-4 expression, but it did have a positive effect on TNFa expression suggesting ERa/ERb competition for ligand binding, similar to the case of IFNg.…”

“…Male T cells already produced higher IFNg and granzyme B due to a higher overall CD8:CD4 T-cell ratio. 100 Estrogen Effect on CD8 þ T-Cell Polyfunctionality Polyfunctionality of CD8 þ T cells is critical in generating superior immune responses against bacterial and viral infections, and more importantly against cancer. It was shown that at baseline estrogen treatment, female Ag-specific T cells are overall more polyfunctional than male T cells in response to Ag-stimulation.…”

Oestrogen amplifies pre‐existing atopy‐associated Th2 bias in an experimental asthma model

“…In addition to effects on DC, oestrogen may also influence T cell development 44 and the balance of CD4/CD8 activation. 45 Although CD4 + Tregs were responding to OVA across all groups, only in males were CD8 + T effector cells observed to respond. As CD8 + and CD4 + T cell populations can potentially cross-regulate each other, notably via the effects of Treg cells that are highly active in rats, the absence of CD8 activation in females and E2-treated males may result in excessive CD4 activation and subsequent Th2 inflammation in these groups, but this possibility was not tested.…”

“…It may also relate to the stable administration of E2 compared to the fluctuating levels in females as part of their oestrous cycle or the length of E2 administration. In addition to effects on DC, oestrogen may also influence T cell development and the balance of CD4/CD8 activation . Although CD4 + Tregs were responding to OVA across all groups, only in males were CD8 + T effector cells observed to respond.…”