Estrogens, Cancer and Immunity

Abstract

Sex hormones are included in many physiological and pathological pathways. Estrogens belong to steroid hormones active in female sex. Estradiol (E2) is the strongest female sex hormone and, with its receptors, contributes to oncogenesis, cancer progression and response to treatment. In recent years, a role of immunosurveillance and suppression of immune response in malignancy has been well defined, forming the basis for cancer immunotherapy. The interplay of sex hormones with cancer immunity, as well as the response to immune checkpoint inhibitors, is of interest. In this review, we investigate the impact of sex hormones on natural immune response with respect to main active elements in anticancer immune surveillance: dendritic cells, macrophages, lymphocytes and checkpoint molecules. We describe the main sex-dependent tumors and the contribution of estrogen in their progression, response to treatment and especially modulation of anticancer immune response.

Keywords: cancer; estrogens; immunity.

Figure 1

Synthesis of sex hormones. Abbreviations: 3β: hydroxysteroid dehydrogenase; 17β: hydroxysteroid dehydrogenase type 1; CYP17: 17a-hydroxylase; DHT: 5α-dihydrotestosterone; DHEA: dehydroepiandrosterone; DHEAS: dehydroepiandrosterone sulfate; P450scc: cytochrome P450 side-chain cleavage enzyme; STS: steroid sulfatase.

Figure 2

Diseases related to estrogen balance with observed prevalence among women. E2: estradiol.

Figure 3

Immune response in cancer depends on tumor characteristics such as molecular alterations and the status of host immunity modified by environmental factors, such as, among others, sex hormones.

Figure 4

Main elements of regulation of immune response and the pathways of immunosuppression in the tumor environment. The anticancer activity of cytotoxic T cells (CTLs) is inhibited (˫) by complex and cooperative cells and mediators. Their activity is plastic and depends on local conditions. Abbreviations: Breg: regulatory B cell; DC: dendritic cell; Treg: regulatory T cell; Foxp3, STAT5, CTLA-4, GITR, PD-1, TIM-3, LAG-3: active molecules on/in Treg; MDSCs: myeloid-derived suppressor cells; M: macrophages; PD-1: programmed death-1; L: ligand; CTLA-4; cytotoxic T cell antigen-4; INFγ: interferon γ; TGF-β; transforming growth factor β.

Figure 5

Simplified summary of the importance of estrogens in tumor immunity. The nature of the tumor environment (TME) is crucial in cancer progression. Many cells (Tregs, Bregs, CD4 and CD8 cells, MDSCs, DCs and cells with PD-1 expression), EMTs and mediators contribute to the immunosuppressive function of the TME. Estrogens, estrogen receptors and enzymes (aromatases) are capable of modifying immune anticancer response. Hormonal balance depends on genetic factors connected with the X chromosome, epigenetics and the environment. Estradiol and estrogen receptor beta are the main players in systemic and local regulation of carcinogenesis, tumor progression and modulation of immunity. Abbreviations: ARO: aromatase; CAF: cancer-associated fibroblast; E2-17β: estradiol; EGFR: epidermal growth factor receptor; ERs: estrogen receptors: EMT: epithelial–mesenchymal transition; M2- type 2 macrophages, MDSCs: myeloid-derived suppressor cells; PD-1 – programmed death, PD-L1: programmed death ligand 1; SASP: senescence-associated secretory phenotype: TEXs: tumor-derived exosomes; TMB: tumor mutational burden; TME: tumor microenvironment, Tregs- regulatory Tcells.