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

Abstract

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 g, interleukin (IL) 6, and tumor necrosis factor a, while testosterone induces IL-10, IL-4, and transforming growth factor b. 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 þ 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.

The Adaptive Immune System in Multiple Sclerosis: An Estrogen-Mediated Point of View

“…The role of ERs in the regulation of the development and functions of innate immune cells has been discussed in detail in other reviews and is beyond the purpose of our manuscript [20,57,58]. However, we report the main findings (summarized in Table 1), especially those linked with MS. Estrogens affect the innate immune system by regulating the number of cells and their specific biological functions: in neutrophils, they regulate chemotaxis, infiltration, and the induction of cytokine-induced neutrophil chemoattractants (e.g., CINC-1, CINC-2β, CINC-3) and cytokines (e.g., TNF-α, IL-6, IL-1β); in macrophages, they regulate chemotaxis, phagocytic activity, and the production of cytokines (e.g., IL-6, TNF-α); in NK cells, they decrease cytotoxicity; in dendritic cells (DCs), they promote differentiation and regulate chemokine (e.g., IL-8 and chemokine C-C motif ligand 2 (CCL2)) and cytokine (e.g., IL-6, IL-10) expression [20,57].…”

“…Increasing evidence is continuing to highlight the action of estrogens on the immune system. These aspects have been described in both physiological (e.g., pregnancy) and pathological conditions of the immune system (e.g., autoimmunity and the tumor microenvironment [57,58]).…”

Sex differences in cancer mechanisms

“…Interestingly, similar E2-mediated EPC mobilization was also observed in male mice with hindlimb ischemia [356,365]; additionally, a higher number of EPCs were observed in men with cardiovascular diseases than agematched women [357], suggesting hormonal regulated angiogenesis may be confounded by cardiovascular diseases. In addition to ECs and EPCs, emerging evidences show that estrogen has an effect on a wide variety of cells in the perivascular environment, including tumor cells, smooth muscle cells, fibroblasts, pericytes, macrophages, and adipose tissue, which can indirectly upregulate angiogenesis by induction of pro-angiogenic factors such as VEGF [366][367][368][369]. Together, these estrogenmediated pro-angiogenic effects align with preclinical and clinical evidence, where a positive correlation between ER expression, angiogenic activity, tumor size, and invasiveness was observed for several cancer types, including breast cancer and lung cancer [350,[370][371][372].…”

The Role of Immune Cells in Breast Tissue and Immunotherapy for the Treatment of Breast Cancer

“…Ultimately, the response of immune cells will also be influenced by cell density, estrogen levels, ECM composition, blood supply, and the specific ER stimulated. 38,40 Although estrogens are probably the major steroid that influences cell behavior, it is recognized that these cells may also contain receptors for other steroids, including progesterone, glucocorticoids, and androgens, 38 and respond and be influenced by these hormones as well. Together, the cellular responsiveness of immune cells to estrogens (and other hormones) further clarifies events regulating progression in carcinogenesis, as well as suggest an additional potentially important role for antiestrogen therapy.…”