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

Epidemiologic studies demonstrate significant gender-specific differences in immune system function. Males are more prone to infection and malignancies, while females are more vulnerable to autoimmune diseases. These differences are thought to be due to the action of gonadal hormones: Estrogen increases the inflammatory response and testosterone dampens it. More specifically, estrogen stimulation induces inflammatory cytokine production including interferon γ, interleukin (IL) 6, and tumor necrosis factor α, while testosterone induces IL-10, IL-4, and transforming growth factor β. More recent studies demonstrate threshold effects of estrogen stimulation on immune cell function: physiologic doses of estrogen (approximately 0.5 nmol/L) stimulate inflammatory cytokine production, but superphysiologic dosages (above 50 nmol/L) can result in decreased inflammatory cytokine production. This review reports findings concerning the impact of estrogen on CD8+ cytotoxic T cells and the overall immune response in the tumor microenvironment. Variables examined include dosage of hormone, the diversity of immune cells involved, and the nature of the immune response in cancer. Collective review of these points may assist in future hypotheses and studies to determine sex-specific differences in immune responses that may be used as targets in disease prevention and treatment.