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

doi:10.1016/j.isci.2023.108401

TRAIL-dependent apoptosis of peritoneal mesothelial cells by NK cells promotes ovarian cancer invasion

iScience. 2023 Nov 7;26(12):108401. doi: 10.1016/j.isci.2023.108401. eCollection 2023 Dec 15.

Authors

Anna Mary Steitz¹, Clarissa Schröder¹, Isabel Knuth¹, Corinna U Keber², Leah Sommerfeld¹, Florian Finkernagel¹, Julia M Jansen³, Uwe Wagner³, Sabine Müller-Brüsselbach¹, Thomas Worzfeld⁴, Magdalena Huber⁵, Vanessa M Beutgen^{6

7}, Johannes Graumann^{6

7}, Elke Pogge von Strandmann⁸, Rolf Müller¹, Silke Reinartz¹

Affiliations

¹ Translational Oncology Group, Center for Tumor Biology and Immunology (ZTI), Philipps University, 35043 Marburg, Germany.
² Institute for Pathology, Philipps University, 35043 Marburg, Germany.
³ Clinic for Gynecology, Gynecological Oncology, Gynecological Endocrinology, University Hospital (UKGM), 35043 Marburg, Germany.
⁴ Institute of Pharmacology, Biochemical-Pharmacological Center (BPC), Philipps University, 35043 Marburg, Germany.
⁵ Institute of Systems Immunology, Center for Tumor Biology and Immunology (ZTI), Philipps University, 35043 Marburg, Germany.
⁶ Institute of Translational Proteomics, Philipps University, 35043 Marburg, Germany.
⁷ Core Facility Translational Proteomics, Philipps University, 35043 Marburg, Germany.
⁸ Institute for Tumor Immunology, Center for Tumor Biology and Immunology (ZTI), Clinic for Hematology, Oncology and Immunology, Philipps University, 35043 Marburg, Germany.

Abstract

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.

Keywords: Cancer; Immunology; Microenvironment.