Let's talk about sex: A biological variable in immune response against melanoma

Abstract

As science culture gravitates toward a more holistic inclusion of both males and females in research design, the outlining of sex differences and their respective intersections with disease physiology and pathophysiology should see reciprocal expansion. Melanoma skin cancer, for example, has observed a female advantage in incidence, mortality, and overall survival since the early 1970s. The exact biological mechanism of this trend, however, is unclear and further complicated by a layering of clinical variables such as skin phototype, age, and body mass index. In this perspective, we highlight epidemiological evidence of sex differences in melanoma and summarize the landscape of their potential origin. Among several biological hallmarks, we make a note of sex-specific immune profiles-along with divergent hormonal regulation, social practices, DNA damage and oxidative stress responses, body composition, genetic variants, and X-chromosome expression-as probable drivers of disparity in melanoma initiation and progression. This review further focuses the conversation of sex as an influencing factor in melanoma development and its potential implication for disease management and treatment strategies.

Keywords: female; immune; male; melanoma; sex.

FIGURE 1

Incidence and US mortality rates for melanoma by sex from 1975–2017. (a) Melanoma Observed (triangle) and Delay‐Adjusted (circle) Incidence are derived from the SEER 9 database and US Mortality Rates (square) from the National Center for Health Statistics (CDC). Male and Female data are visualized as blue and pink, respectively. Rates are age‐adjusted to the 2000 US Standard Population (19 age groups, Census P25‐1103) and only consider Caucasian individuals. Regression lines and Annual Percentage Changes (APCs) are modeled from Joinpoint Regression Program Version 4.8, April 2020, National Cancer Institute—estimations are shown as a solid line for delay‐adjusted incidence and a dashed line for observed incidence and mortality. APC represents Annual Percent Change for the regression lines, and those with an asterisk (*) indicate significant deviations from zero for p < 0.05. (b) Survival data were collected from cBioPortal for patients of all ages, and Kaplan‐Meier analysis was performed in R showing overall survival probability. Respective confidence intervals are represented as blue and pink dashed lines. Black dashed lines indicate median survival for each sex (M: 92.76, F: 124.88). The cBioPortal database was filtered for non‐redundant melanoma data, with a tally of 17 studies and 2667 patients. This subset was further filtered for cutaneous melanoma (72.1% of patients) reducing the sample size to 1956 patients. Patients were then grouped by sex and availability of overall survival status, with an exclusion of NA or unlabeled individuals, and Kaplan–Meier survival analysis completed with 540 females and 996 males

FIGURE 2

Potential hallmarks of sex differences in melanoma. A summary of the possible driving factors of sex differences in melanoma. For each hallmark, the major reported finding as seen between males and females is stated. Not every hallmark is known to be associated with melanoma but can be hypothesized. The numbering system corresponds to the order in which topics are discussed in this article