Mikulak Joanna, Terzoli Sara, Marzano Paolo, Cazzetta Valentina, Martiniello Giampaolo, Piazza Rocco, Viano Maria Estefania, Vitobello Domenico, Portuesi Rosalba, Grizzi Fabio, Hegazi Mohamed A A A, Fiamengo Barbara, Basso Gianluca, Parachini Lara, Mannarino Laura, D'Incalci Maurizio, Marchini Sergio, Mavilio Domenico
Laboratory of Clinical and Experimental Immunology, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy.
Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy.
Cell Death Dis. 2025 Apr 1;16(1):229. doi: 10.1038/s41419-025-07557-5.
The mechanisms driving immune evasion in early-stage I high-grade serous ovarian carcinoma (HGSOC) remain poorly understood. To investigate this, we performed single-cell RNA-sequencing analysis. Our findings revealed a highly immunosuppressive HGSOC microenvironment, characterized by abundant infiltration of regulatory T cells (Tregs). Trajectory analysis uncovered differentiation pathways of naïve Tregs, which underwent either activation and proliferation or transcriptional instability. The predicted Treg-cell interaction network, including crosstalk within tumor cells, facilitates Treg mobility and maturation while reinforcing their immunosuppressive function and persistence in the tumor. Moreover, their interactions with immune cells likely inhibit CD8 T cells and antigen-presenting cells, supporting tumor immune escape. Additionally, more immunogenic tumor conditions, marked by IFNγ production, may contribute to Treg destabilization. Our findings underscore the pivotal role of Tregs in early immune evasion of HGSOC and provide insights into potential therapeutic strategies targeting their activity and differentiation fate.
早期I期高级别浆液性卵巢癌（HGSOC）中驱动免疫逃逸的机制仍知之甚少。为了对此进行研究，我们进行了单细胞RNA测序分析。我们的研究结果揭示了一种高度免疫抑制的HGSOC微环境，其特征是调节性T细胞（Tregs）大量浸润。轨迹分析揭示了幼稚Tregs的分化途径，其经历了激活和增殖或转录不稳定性。预测的Treg细胞相互作用网络，包括肿瘤细胞内的串扰，促进了Tregs的迁移和成熟，同时增强了它们在肿瘤中的免疫抑制功能和持久性。此外，它们与免疫细胞的相互作用可能会抑制CD8 T细胞和抗原呈递细胞，支持肿瘤免疫逃逸。此外，以产生IFNγ为特征的更多免疫原性肿瘤状态可能导致Treg不稳定。我们的研究结果强调了Tregs在HGSOC早期免疫逃逸中的关键作用，并为针对其活性和分化命运的潜在治疗策略提供了见解。
