TRAIL-dependent apoptosis of peritoneal mesothelial cells by NK cells promotes ovarian cancer invasion
Anna Mary Steitz,
Clarissa Schröder,
Isabel Knuth,
Corinna U. Keber,
Leah Sommerfeld,
Florian Finkernagel,
Julia M. Jansen,
Uwe Wagner,
Sabine Müller-Brüsselbach,
Thomas Worzfeld,
Magdalena Huber,
Vanessa M. Beutgen,
Johannes Graumann,
Elke Pogge von Strandmann,
Rolf Müller,
Silke Reinartz
Affiliations
Anna Mary Steitz
Translational Oncology Group, Center for Tumor Biology and Immunology (ZTI), Philipps University, 35043 Marburg, Germany
Clarissa Schröder
Translational Oncology Group, Center for Tumor Biology and Immunology (ZTI), Philipps University, 35043 Marburg, Germany
Isabel Knuth
Translational Oncology Group, Center for Tumor Biology and Immunology (ZTI), Philipps University, 35043 Marburg, Germany
Corinna U. Keber
Institute for Pathology, Philipps University, 35043 Marburg, Germany
Leah Sommerfeld
Translational Oncology Group, Center for Tumor Biology and Immunology (ZTI), Philipps University, 35043 Marburg, Germany
Florian Finkernagel
Translational Oncology Group, Center for Tumor Biology and Immunology (ZTI), Philipps University, 35043 Marburg, Germany
Julia M. Jansen
Clinic for Gynecology, Gynecological Oncology, Gynecological Endocrinology, University Hospital (UKGM), 35043 Marburg, Germany
Uwe Wagner
Clinic for Gynecology, Gynecological Oncology, Gynecological Endocrinology, University Hospital (UKGM), 35043 Marburg, Germany
Sabine Müller-Brüsselbach
Translational Oncology Group, Center for Tumor Biology and Immunology (ZTI), Philipps University, 35043 Marburg, Germany
Thomas Worzfeld
Institute of Pharmacology, Biochemical-Pharmacological Center (BPC), Philipps University, 35043 Marburg, Germany
Magdalena Huber
Institute of Systems Immunology, Center for Tumor Biology and Immunology (ZTI), Philipps University, 35043 Marburg, Germany
Vanessa M. Beutgen
Institute of Translational Proteomics, Philipps University, 35043 Marburg, Germany; Core Facility Translational Proteomics, Philipps University, 35043 Marburg, Germany
Johannes Graumann
Institute of Translational Proteomics, Philipps University, 35043 Marburg, Germany; Core Facility Translational Proteomics, Philipps University, 35043 Marburg, Germany
Elke Pogge von Strandmann
Institute for Tumor Immunology, Center for Tumor Biology and Immunology (ZTI), Clinic for Hematology, Oncology and Immunology, Philipps University, 35043 Marburg, Germany
Rolf Müller
Translational Oncology Group, Center for Tumor Biology and Immunology (ZTI), Philipps University, 35043 Marburg, Germany; Corresponding author
Silke Reinartz
Translational Oncology Group, Center for Tumor Biology and Immunology (ZTI), Philipps University, 35043 Marburg, Germany; Corresponding author
Summary: A crucial requirement for metastasis formation in ovarian high-grade serous carcinoma (HGSC) is the disruption of the protective peritoneal mesothelium. Using co-culture systems of primary human cells, we discovered that tumor-associated NK cells induce TRAIL-dependent apoptosis in mesothelial cells via death receptors DR4 and DR5 upon encounter with activated T cells. Upregulation of TRAIL expression in NK cells concomitant with enhanced cytotoxicity toward mesothelial cells was driven predominantly by T-cell-derived TNFα, as shown by affinity proteomics-based analysis of the T cell secretome in conjunction with functional studies. Consistent with these findings, we detected apoptotic mesothelial cells in the peritoneal fluid of HGSC patients. In contrast to mesothelial cells, HGSC cells express negligible levels of both DR4 and DR5 and are TRAIL resistant, indicating cell-type-selective killing by NK cells. Our data point to a cooperative action of T and NK in breaching the mesothelial barrier in HGSC patients.
