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

被引：0

作者：

Maas, Ralph J. A. ^{[1
]}

Hoogstad-van Evert, Janneke S. ^{[1
,2
]}

Hagemans, Iris M. ^{[1
]}

Brummelman, Jolanda ^{[1
]}

van Ens, Diede ^{[1
]}

de Jonge, Paul K. J. D. ^{[1
]}

Hooijmaijers, Laura ^{[1
]}

Mahajan, Shweta ^{[1
]}

van der Waart, Anniek B. ^{[1
]}

Hermans, Charlotte K. J. C. ^{[1
]}

de Klein, Janne ^{[1
]}

Woestenenk, Rob ^{[1
]}

van Herwaarden, Antonius E. ^{[3
]}

Schaap, Nicolaas P. M. ^{[4
]}

Rezaeifard, Somayeh ^{[1
,5
]}

Tauriello, Daniele V. F. ^{[5
]}

Zusterzeel, Petra L. M. ^{[6
]}

Ottevanger, Nelleke ^{[7
]}

Jansen, Joop H. ^{[1
]}

Hobo, Willemijn ^{[1
]}

Dolstra, Harry ^{[1
]}

机构：

[1] Radboud Univ Nijmegen Med Ctr, Dept Lab Med, Lab Hematol, Nijmegen, Netherlands

[2] Dept Obstet & Gynecol Amphia, Breda, Netherlands

[3] Radboud Univ Nijmegen Med Ctr, Dept Lab Med, Diagnost Lab, Nijmegen, Netherlands

[4] Radboud Univ Nijmegen Med Ctr, Dept Hematol, Nijmegen, Netherlands

[5] Radboud Univ Nijmegen Med Ctr, Dept Cell Biol, Nijmegen, Netherlands

[6] Radboud Univ Nijmegen Med Ctr, Dept Obstet & Gynecol, Nijmegen, Netherlands

[7] Radboud Univ Nijmegen Med Ctr, Dept Med Oncol, Nijmegen, Netherlands

来源：

FRONTIERS IN IMMUNOLOGY | 2024年 / 15卷

关键词：

ovarian cancer; ascites; natural killer (NK) cells; TGF-beta; tumor microenvironment; REGULATORY T-CELLS; GROWTH-FACTOR-BETA; KILLER-CELLS; TUMOR; CYTOKINES;

D O I：

10.3389/fimmu.2024.1448041

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

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)-beta 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-beta 1 exposure. Moreover, inhibition of TGF-beta 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-beta 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-beta 1 signaling could increase NK cell immune responses in high-grade EOC patients.

引用

页数：15