Single-cell RNA sequencing analysis reveals the immune-suppressive tumor microenvironment in Stage-I High-Grade Serous Ovarian Carcinoma

High-grade serous ovarian carcinoma is the predominant and deadliest subtype of ovarian cancer, often diagnosed at advanced stages due to the asymptomatic nature of its early stages1,2. Notably, the advanced stages of the disease are characterized by a significant presence of immunosuppressive cells in the tumor microenvironment, contributing to the creation of a hostile environment that hampers the effectiveness of the immune system3. However, the mechanisms behind the immune-suppressive dynamics in the early-stage are still poorly investigated. Therefore, we investigated the tumor microenvironment through a single-cell RNA sequencing analysis of tumor-associated immune CD45+ cells, their CD45- counterpart, and matched blood circulating immune cells from two incidentally stage-I diagnosed patients who underwent surgery without prior chemotherapy treatment. Our findings indicated an immune-suppressive tumor microenvironment characterized by the enrichment of regulatory T cells. Tumor-infiltrating regulatory T cells exhibited distinct stages of differentiation and effector profiles, associated with transcriptomic patterns of naive, effector, proliferating, and destabilized states. Trajectory analysis delineated two differentiation paths for regulatory T cells that on the one hand result in hyperactivation and proliferation and the other in transcriptional instability, functional re-specialization, and exhaustion. These findings contribute significantly to the understanding of the microenvironment of stage-I High-grade serous ovarian carcinoma, emphasizing the role of regulatory T cells in tumor immune evasion and suggesting regulatory T cells as a possible therapeutic target that can hinder their immunosuppressive activity and inhibit tumor progression.