高级别上皮性卵巢癌中腹腔 TGF-β1 升高与腹水诱导的 NK 细胞功能障碍和生存期缩短的相关性

Natural killer (NK) cell therapy represents an attractive immunotherapy approach against recurrent epithelial ovarian cancer (EOC), as EOC is sensitive to NK cell-mediated cytotoxicity.

However, NK cell antitumor activity is dampened by suppressive factors in EOC patient ascites.

Here, we integrated functional assays, soluble factor analysis, high-dimensional flow cytometry cellular component data and clinical parameters of advanced EOC patients to study the mechanisms of ascites-induced inhibition of NK cells.

Using a suppression assay, we found that ascites from EOC patients strongly inhibits peripheral blood-derived NK cells and CD34+ progenitor-derived NK cells, albeit the latter were more resistant. Interestingly, we found that higher ascites-induced NK cell inhibition correlated with reduced progression-free and overall survival in EOC patients.

Furthermore, we identified transforming growth factor (TGF)- 1 to correlate with ascites-induced NK cell dysfunction and reduced patient survival. In functional assays, we showed that proliferation and anti-tumor reactivity of CD34+ progenitor-derived NK cells are significantly affected by TGF- 1 exposure.

Moreover, inhibition of TGF- 1 signaling with galunisertib partly restored NK cell functionality in some donors. For the cellular components, we showed that the secretome is associated with a different composition of CD45+ cells between ascites of EOC and benign reference samples with higher proportions of macrophages in the EOC patient samples.

Furthermore, we revealed that higher TGF- 1 levels are associated with the presence of M2-like macrophages, B cell populations and T-regulatory cells in EOC patient ascites.

These findings reveal that targeting TGF- 1 signaling could increase NK cell immune responses in high-grade EOC patients.