D3.393 - Immunological Profiling of the Kras-Driven Microenvironment in a Murine Model of Endometriosis

Endometriosis is a chronic inflammatory disease characterized by the ectopic growth of endometrial-like tissue outside the uterine cavity. Oncogenic mutations in Kirsten rat sarcoma viral oncogene homolog (KRAS), particularly the KRAS^G12D allele, are recognized as pivotal drivers of cellular transformation. Given that KRAS mutations occur in the epithelium of both healthy endometrium and endometrial malignancies, suggesting that KRAS mutation may be involved in the development of endometriosis. they are hypothesized to play a significant role in the pathogenesis of endometriosis. In this study, we investigated how oncogenic KRAS^G12D affects endometriosis lesion growth and the immune microenvironment in a murine model. This study aimed to characterize the immune cell profile within the Kras^G12D-associated microenvironment and evaluate its influence on lesion progression in a murine model.

To simulate the ectopic growth characteristic of the disease, a surgically induced endometriosis model was established by transplanting uterine tissues from Kras^G12D-mutant donors into wild-type recipients. At the experimental endpoint, lesion weights and survival rates were assessed. The immune cell composition within the lesions was further analyzed using multiparametric flow cytometry.

Lesions derived from Kras^G12D-mutant tissues exhibited hallmark pathological features, including squamous metaplasia and intensified immune cell infiltration. Immunohistochemical analysis confirmed that mutant Kras^G12D protein was predominantly localized to epithelial regions of the lesions. Notably, compared with wild-type controls, Kras^G12D tissues showed significantly increased lesion weight and enhanced immune cell infiltration. Specifically, a marked reduction in CD8^⁺ T cells abundance was identified, indicating a distinct shift in lymphocyte subset composition. Furthermore, while a significant negative correlation between CD8^⁺ T cell number and lesion size existed in the wild-type group, this relationship was absent in the Kras^G12D group.

These findings indicate that oncogenic Kras^G12D expression in uterine epithelial cells may promote endometriotic lesion growth and alter the immune microenvironment, specifically by diminishing CD8^⁺ T cell infiltration and impairing immune-mediated growth control. These results suggest that Kras^G12D-driven chronic inflammation is a key factor in the immune dysregulation during endometriosis development.