Immune Suppression and Somatic Mutation in Endometriosis – An Opportunity for Personalized Immunotherapy

Daniel J Park,1 Bernard J Pope1,21Melbourne Bioinformatics, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, VIC, Australia; 2Department of Surgery, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, VIC, AustraliaCorrespondence: Daniel J Park, Email [email protected]: Endometriosis is a chronic, inflammatory condition affecting around 10% of reproductive-age women, characterized by the presence of endometrial-like tissue outside of the uterus. The effects of endometriosis include chronic pelvic pain, menorrhagia and infertility. Despite its prevalence and impact, current therapies remain limited in efficacy and scope. Recent insights into the immunological landscape of endometriosis along with the discovery of common somatic mutations open the door to new ways of thinking about therapies for endometriosis. Individual endometrial glands have been shown to carry distinct cancer-associated somatic mutations, suggesting a mosaic architecture. Clonal selection during retrograde dissemination and lesion establishment is evident such that genetic and epigenetic alterations appear to confer survival advantages. Immune suppression is another characteristic of the endometriotic environment, with evidence including observations of elevated checkpoint molecules in lesions. Here, we propose a future therapeutic framework based on checkpoint inhibition in combination with personalized vaccination targeting patient-specific neoantigens. This perspective integrates immunological, molecular, and clinical insights to propose a novel therapeutic direction. Importantly, the therapeutic framework described herein should be regarded as a hypothesis-generating perspective rather than a clinically validated treatment strategy. While evidence supports immune dysregulation and recurrent somatic mutation in endometriosis, substantial biological, translational and clinical uncertainties remain before mutation-directed immunotherapy could be considered feasible in clinical practice.Keywords: checkpoint inhibition, endometriosis, immune suppression, immunotherapy, mRNA vaccine, neoantigens, personalized vaccine