Journal Article

Increased peritoneal TGF-β1 is associated with ascites-induced NK-cell dysfunction and reduced survival in high-grade epithelial ovarian cancer

Mahajan, Shweta, Brummelman, Jolanda, van Ens, Diede, Zusterzeel, Petra L. M., Hoogstad-van Evert, Janneke S., de Klein, Janne, Schaap, Nicolaas P. M., Hagemans, Iris M., Ottevanger, Nelleke, Jansen, Joop H., Dolstra, Harry, Tauriello, Daniele V. F., van Herwaarden, Antonius E., Hobo, Willemijn, Woestenenk, Rob, van der Waart, Anniek B., Hermans, Charlotte K. J. C., Rezaeifard, Somayeh, Maas, Ralph J. A., Hooijmaijers, Laura, de Jonge, Paul K. J. D.

2024

Overview

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)-β1 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-β1 exposure. Moreover, inhibition of TGF-β1 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-β1 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-β1 signaling could increase NK cell immune responses in high-grade EOC patients.

• Publisher: Frontiers Media SA,Frontiers Media S.A
• Subject: Abdomen / Aged / Antitumor activity / Ascites / Ascites - immunology / Carcinoma, Ovarian Epithelial - immunology / Carcinoma, Ovarian Epithelial - mortality / CD34 antigen / CD45 antigen / Cell culture / Cell proliferation / Cell survival / Cell therapy / Cytotoxicity / Data analysis / Discriminant analysis / Factor analysis / Female / Flow cytometry / Hemopoiesis / Humans / Immune response / Immune response (cell-mediated) / Immunology / Immunoregulation / Immunotherapy / Killer Cells, Natural - immunology / Killer Cells, Natural - metabolism / Lymphocytes T / Macrophages / Medical prognosis / Medical research / Middle Aged / natural killer (NK) cells / Natural killer cells / Neoplasm Grading / Ovarian cancer / Ovarian Neoplasms - immunology / Ovarian Neoplasms - mortality / Ovarian Neoplasms - pathology / Patients / Peripheral blood / Progenitor cells / Pyrazoles - pharmacology / Pyrazoles - therapeutic use / Quinolines / Research ethics / Secretome / Surgery / TGF-β / Transforming Growth Factor beta1 - metabolism / Transforming growth factor-b1 / tumor microenvironment