Serum CD95L level correlates with tumor immune infiltration and is a positive prognostic marker for advanced high grade serous ovarian cancer

Soluble CD95L (s-CD95L) is a chemoattractant for certain lymphocyte subpopulations. We examined whether this ligand is a prognostic marker for high grade serous ovarian cancer (HGSOC) and whether it is associated with accumulation of immune cells in the tumor. Serum s-CD95L levels in 51 patients with advanced ovarian cancer were tested by ELISA. Immunohistochemical staining of CD3, CD4, CD8, CD20, CD163, CD31, FoxP3, CCR6, IL-17, Granzyme B, PD-L1, and membrane CD95L was used to assess tumor-infiltrating immune cells. Although the intensity of CD3, CD8, CD4, CD20, and CD163 in tumor tissues remained constant regardless of membrane CD95L expression, tumors in HGSOC patients with s-CD95L levels > 516 pg/ml showed increased infiltration by CD3+ T cells (p = 0.001), comprising both cytotoxic CD8+ (p = 0.01) and CD4+ (p = 0.0062) cells including FoxP3+ regulatory T cells (p = 0.0044). Also, the number of tumor-infiltrating CD20+ B cells (p = 0.0094) increased in these patients. Multivariate analyses revealed that low s-CD95L concentrations ( 6000 CD3+ cells (HR, 0.34; 95% CI, 0.15-0.79) was a good prognostic factor. Thus, low levels of s-CD95L (<516 pg/mL) are correlated with lower numbers of tumor-infiltrating lymphocytes (CD3+ and CD8+, but also CD4 and FoxP3 T cells) in advanced HGSOC and are a poor prognostic marker. Implications: Serum s-CD95L is correlated with the number of tumor-infiltrating immune cells in HGSOC and could be used as a non-invasive marker of tumor immune infiltration to select patients referred for immunotherapy trials that evaluate checkpoint inhibitor treatment.