Studies of sex immune dimorphism in the tumor microenvironment – Towards genderized immunotherapy 4837

Abstract Description Precision medicine, which tailors strategies to individual tumor characteristics, is transforming cancer treatment. Immunotherapy, targeting immune suppression in the tumor microenvironment (TME) to activate cytotoxic immune cells, shows great promise. However, sex-specific immune responses in the TME are poorly understood, partly due to the underrepresentation of women in clinical trials, leading to generalized treatments that overlook key differences. To explore sex-specific differences driving immunosuppression and tumor progression, we analyzed data from 172 pancreatic ductal adenocarcinoma (PDAC) patients using bulk and single-cell transcriptomics, proteomics, and functional assays. We identified a macrophage subpopulation linked to immune-exclusive tumor phenotypes, immune cell dysfunction, and metastasis, driven by the G-protein coupled receptor FPR2. FPR2 expression correlated with poor outcomes in females but not males, underscoring sex-specific TME influences. Single-cell analyses revealed distinct immune landscapes: females had reduced NK cells and increased Th17 cells, while males exhibited reduced Th1 cells. Chromosomal region differences extended beyond sex chromosomes. These findings reveal critical sex-based discrepancies shaping the TME, highlighting the need for tailored therapies. We are developing immunotherapy antibodies for women with PDAC, advancing “genderized medicine” to improve outcomes through personalized, sex-specific strategies. Funding Sources Swedish Cancer Society Karolinska Institutets funds Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)