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<p>The tumor microenvironment of epithelial ovarian cancer (EOC) malignant ascites remains incompletely characterized, particularly regarding CD8<sup>+</sup> T lymphocyte differentiation and metabolic adaptations. This study investigated these characteristics and their relationship with estrogen receptor (ER) expression in 40 treatment-naïve EOC patients. Matched ascitic fluid and peripheral blood samples underwent comprehensive multicolor flow cytometric analysis to evaluate programmed death-1 (PD-1) expression, differentiation subset distribution, and mitochondrial functional parameters. CD8<sup>+</sup> T lymphocytes demonstrated substantial enrichment among the lymphocyte population in ascitic fluid (27.9 ± 2.0%) compared to peripheral blood (13.1 ± 1.3%, <i>p</i> &lt; 0.0001), accompanied by elevated PD-1 expression (62.4 ± 2.9% versus 40.9 ± 2.1%, <i>p</i> &lt; 0.0001). Effector memory populations (Tem) predominated within ascites (67.9 ± 2.8%), indicating chronic antigenic exposure. Mitochondrial functional assessment revealed a distinctive metabolic phenotype: despite preserved mitochondrial mass, ascitic CD8<sup>+</sup> T lymphocytes exhibited significantly reduced mitochondrial calcium (Rhod-2 positivity: 44.7 ± 3.8% versus 68.2 ± 4.5%, <i>p</i> &lt; 0.0001) and reactive oxygen species (MitoSOX positivity: 18.7 ± 2.2% versus 28.9 ± 3.0%, <i>p</i> = 0.0287). Notably, ER-positive tumors (≥ 50% immunohistochemical expression) correlated with reduced frequency of CD8<sup>+</sup> T cells among lymphocytes (22.1 ± 2.2% versus 32.5 ± 2.9%, <i>p</i> = 0.0040) and decreased PD-1 expression (55.7 ± 3.4% versus 74.5 ± 2.5%, <i>p</i> = 0.0003), while maintaining elevated mitochondrial mass (MTG positivity: 77.3 ± 2.8% versus 43.4 ± 6.9%, <i>p</i> &lt; 0.0001). These findings indicate ascitic CD8<sup>+</sup> T lymphocytes undergo metabolic reprogramming characterized by minimized mitochondrial stress, potentially representing an adaptive survival mechanism within the hostile ascitic microenvironment. The differential immune phenotypes associated with ER expression suggest distinct immune evasion strategies requiring tailored therapeutic approaches. This comprehensive characterization provides critical insights for developing personalized immunotherapeutic strategies incorporating metabolic modulation and hormone receptor status stratification.</p>

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Differentiation and mitochondrial metabolic characteristics of CD8+ T cells in malignant ascites of epithelial ovarian cancer and their correlation with estrogen signaling

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月29日

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  • Zouyu Jiang,
  • Ying Zhou,
  • Jiajuan Wu,
  • Yu Shen,
  • Danni Tang,
  • Yuhong Wu,
  • Qiuxia Qu,
  • Juan Wang

摘要

The tumor microenvironment of epithelial ovarian cancer (EOC) malignant ascites remains incompletely characterized, particularly regarding CD8+ T lymphocyte differentiation and metabolic adaptations. This study investigated these characteristics and their relationship with estrogen receptor (ER) expression in 40 treatment-naïve EOC patients. Matched ascitic fluid and peripheral blood samples underwent comprehensive multicolor flow cytometric analysis to evaluate programmed death-1 (PD-1) expression, differentiation subset distribution, and mitochondrial functional parameters. CD8+ T lymphocytes demonstrated substantial enrichment among the lymphocyte population in ascitic fluid (27.9 ± 2.0%) compared to peripheral blood (13.1 ± 1.3%, p < 0.0001), accompanied by elevated PD-1 expression (62.4 ± 2.9% versus 40.9 ± 2.1%, p < 0.0001). Effector memory populations (Tem) predominated within ascites (67.9 ± 2.8%), indicating chronic antigenic exposure. Mitochondrial functional assessment revealed a distinctive metabolic phenotype: despite preserved mitochondrial mass, ascitic CD8+ T lymphocytes exhibited significantly reduced mitochondrial calcium (Rhod-2 positivity: 44.7 ± 3.8% versus 68.2 ± 4.5%, p < 0.0001) and reactive oxygen species (MitoSOX positivity: 18.7 ± 2.2% versus 28.9 ± 3.0%, p = 0.0287). Notably, ER-positive tumors (≥ 50% immunohistochemical expression) correlated with reduced frequency of CD8+ T cells among lymphocytes (22.1 ± 2.2% versus 32.5 ± 2.9%, p = 0.0040) and decreased PD-1 expression (55.7 ± 3.4% versus 74.5 ± 2.5%, p = 0.0003), while maintaining elevated mitochondrial mass (MTG positivity: 77.3 ± 2.8% versus 43.4 ± 6.9%, p < 0.0001). These findings indicate ascitic CD8+ T lymphocytes undergo metabolic reprogramming characterized by minimized mitochondrial stress, potentially representing an adaptive survival mechanism within the hostile ascitic microenvironment. The differential immune phenotypes associated with ER expression suggest distinct immune evasion strategies requiring tailored therapeutic approaches. This comprehensive characterization provides critical insights for developing personalized immunotherapeutic strategies incorporating metabolic modulation and hormone receptor status stratification.