Sex and Gender Disparities in Melanoma

Abstract

Worldwide, the total incidence of cutaneous melanoma is higher in men than in women, with some differences related to ethnicity and age and, above all, sex and gender. Differences exist in respect to the anatomic localization of melanoma, in that it is more frequent on the trunk in men and on the lower limbs in women. A debated issue is if-and to what extent-melanoma development can be attributed to gender-specific behaviors or to biologically intrinsic differences. In the search for factors responsible for the divergences, a pivotal role of sex hormones has been observed, although conflicting results indicate the involvement of other mechanisms. The presence on the X chromosome of numerous miRNAs and coding genes playing immunological roles represents another important factor, whose relevance can be even increased by the incomplete X chromosome random inactivation. Considering the known advantages of the female immune system, a different cancer immune surveillance efficacy was suggested to explain some sex disparities. Indeed, the complexity of this picture emerged when the recently developed immunotherapies unexpectedly showed better improvements in men than in women. Altogether, these data support the necessity of further studies, which consider enrolling a balanced number of men and women in clinical trials to better understand the differences and obtain actual gender-equitable healthcare.

Keywords: immunity; immunotherapy; melanoma; microRNAs; sex-hormones; sex/gender.

Figure 1

Schematic overview of some representative in vivo studies supporting the hormonal involvement in melanoma disease. (Left) Evidences of female hormonal treatments in in vivo mice models. E2 treatment of castrated mice s.c. injected with ER positive melanoma cells reduces tumor growth [47]. 2ME2 treatment of SCID mice, previously intrasplenically injected with melanoma cells, decreases primary tumor growth and liver metastasis number [49]. Treatment of melanoma cells with GPER agonist affects tumor growth in host mice improving response to immunotherapy [54]. Administration of the ERβ agonist LY500307 in female mice, previously i.v. injected with melanoma cells, decreases lung nodules [55]. Oral administration of TAM [56] and EDX [57] exert inhibitory effects on tumor metastatization into the mouse lungs. (Right) AR action is responsible for the increased number of lung metastases through the miR-539-3p/USP13/MITF/AXL axis [58], whereas AR blockade mediates an increase in the immune response [59]. T loss in castrated male mice causes a decrease in the anti-tumor neutrophil function [60]. E2: 17β-estradiol; 2-ME2: 2-methoxyestradiol; TAM: Tamoxifen; EDX: endoxifen; USP13: ubiquitin specific peptidase 13; MITF: microphthalmia-associated transcription factor; AXL: receptor tyrosine kinase AXL; T: testosterone. s.c. subcutaneous, i.v. intravenous.

Figure 2

Key gender-related differences of the immune cell populations involved in melanoma. This representative picture shows the main immune cell populations present with higher frequencies in males (i.e., CD8+, Treg and NK cells [12,123,124,125]) (left) and in female patients (i.e., the immune phenotype enriched in TAA-T cells, CD4+ and DCs cells [80,123,124,126] with higher levels of circulating Interferon I (IFN I) and IFN γ [80,84,85]) (right). NK: natural killer; TAA: tumor-associated antigen; DCs: dendritic cells.

Figure 3

X-linked miRNA mapping and key roles in melanoma development and progression. Schematic depiction of miRNA localization on the human X chromosome: miRNAs with a confirmed role in melanoma pathogenesis are shown. Red writing inside boxes indicate miRNAs, target genes (italics) and their downstream oncogenic effects; green writing indicates those with oncosuppressive functions. PAR1 and 2: pseudoautosomal region 1 and 2; p27^Kip1: cyclin-dependent kinase inhibitor 1B; ETS-1: ETS proto-oncogene 1; SCD5: Stearoyl-CoA Desaturase 5; SWI-SNF: Switch/Sucrose Non-Fermentable; STAT: Signal Transducer and Activator of Transcription; IL-6 and 10: Interleukin 6 and 10; RUNX3: Runt-related transcription factor 3; IKKα: Inhibitory-KB Kinase α; STAT3: Signal Transducer and Activator of Transcription 3; MEF2C: Myocyte Enhancer Factor 2C; C/EBPβ: CCAAT/enhancer-Binding Protein β; E2F1: E2F transcription factor 1; FOXO1: Forkhead Box protein O1; NF1-A: Nuclear Factor 1 A; Wnt-16: Wnt family member 16; AKT1: AKT serine/threonine kinase 1; CDKN1A: Cyclin-Dependent Kinase Inhibitor 1A; Rbp1-like: Retinol Binding Protein 1-like; Hipk3: Homeodomain-Interacting Protein Kinase 3.