Impact of sex on immune-related adverse events in patients with melanoma.
Authors: Ottaviano Margaret , Mallardo Domenico , Vitale Maria Grazia , Vanella Vito , Fordellone Mario , Festino Lucia , Trojaniello Claudia , Sparano Francesca , Facchini Bianca Arianna , Cioli Eleonora , Isaja Antonio , Cavalcanti Ernesta , Capone Mariaelena , Madonna Gabriele , Paone Miriam , Chiodini Paolo , Caraco Corrado , Simeone Ester , Ascierto Paolo Antonio 
Published: July 2024

e21548

Background: The clinical success of immune checkpoint inhibitors (ICIs) has predominantly conquered the modern scenario of the fight against cancer. Sex is a well acknowledged biological variable that affects immune responses to both self and foreign antigens. Indeed, recent meta-analyses of phase II and III trials of ICIs have focused on sex-related prognostic outcomes, reporting that both the overall and the progression-free survival are greater for males than females in melanoma, urothelial, and non-small-cell lung cancer. Conversely, very few studies have investigated the impact of sex on possible correlation with ICIs adverse events (AEs). Aim of this study is to identify female-male (F-M) differences in AEs developed in melanoma patients (pts) during anti-PD-1 treatment and to explore the related biological mechanism through a gene profiling analysis. Methods: Melanoma pts underwent anti-PD-1 delivery as adjuvant as well as first line treatment, who developed AEs from grade 2 onwards, according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, have been involved in the study. Gene profiling analysis was performed using NanoString IO360 panel, RNA was extracted from whole blood. Female-male differences in AEs were tested by Fisher's exact test. Volcano plot was used for graphical gene expression of fold change. Results: A total population of 161 melanoma pts has been analysed. With a total of 73 female pts and 88 male pts, arthralgia and nausea resulted as significant statistically different between female and male (p-value = 0.03 and < 0.01 respectively), with female pts most affected. A specific gene signature in female who developed arthralgia has been identified and characterized by the following genes: BCL2, EGFR, WNT10A, CTSS, IFITM2, HLA-B. These genes are involved in intracellular pro-apoptotic pathways activation and innate and adaptive immune responses activation. It has been already acknowledged that females are able to mount stronger innate and adaptive immune responses than males, which results in faster clearance of pathogens and greater vaccine efficacy in females than in males, but also explains the greater incidence of inflammatory and autoimmune diseases in females. Conclusions: In this study, we found a significant statistically sex difference of arthralgia and nausea during anti- PD-1 treatment in melanoma pts. Arthralgia in female is associated with a peculiar gene signature, which needs further investigation. Greater consideration should be given for researches that address the biological (sex) as well as sociocultural (gender) causes of F-M discrepancies in cancer immunotherapy. International collaborations have to be hugely promoted to increase knowledge in this field.