Mechanisms Driving Neutrophil-Induced T-cell Immunoparalysis in Ovarian Cancer
Abstract
T-cell activation and expansion in the tumor microenvironment (TME) are critical for antitumor immunity. Neutrophils in the TME acquire a complement-dependent T-cell suppressor phenotype that is characterized by inhibition of T-cell proliferation and activation through mechanisms distinct from those of myeloid-derived suppressor cells. In this study, we used ascites fluid supernatants (ASC) from patients with ovarian cancer as an authentic component of the TME to evaluate the effects of ASC on neutrophil function and mechanisms for neutrophil-driven immune suppression. ASC prolonged neutrophil life span, decreased neutrophil density, and induced nuclear hypersegmentation. Mass cytometry analysis showed that ASC induced 15 distinct neutrophil clusters. ASC stimulated complement deposition and signaling in neutrophils, resulting in surface mobilization of granule constituents, including NADPH oxidase. NADPH oxidase activation and phosphatidylserine signaling were required for neutrophil suppressor function, although we did not observe a direct role of extracellular reactive oxygen species in inhibiting T-cell proliferation. Postoperative surgical drainage fluid also induced a complement-dependent neutrophil suppressor phenotype, pointing to this effect as a general response to injury. Like circulating lymphocytes, ASC-activated neutrophils caused complement-dependent suppression of tumor-associated lymphocytes. ASC-activated neutrophils adhered to T cells and caused trogocytosis of T-cell membranes. These injury and signaling cues resulted in T-cell immunoparalysis characterized by impaired NFAT translocation, IL2 production, glucose uptake, mitochondrial function, and mTOR activation. Our results demonstrate that complement-dependent priming of neutrophil effector functions in the TME induces a T-cell nonresponsiveness distinct from established checkpoint pathways and identify targets for immunotherapy.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- May 14, 2021
- Source ID
- 10.1158/2326-6066.cir-20-0922
Entities
People
- Anm Nazmul H. Khan
- Anna Schubart
- Brahm H. Segal
- Cathelijn E M Aarts
- Emese Zsiros
- Holger Sellner
- Ilse Jongerius
- Ivy L. Debreceni
- James A Lederer
- Jason Ricciuti
- Jörg Eder
- Kaitlyn Howard
- Kelly L Singel
- Kevin H Eng
- Kirsten B. Moysich
- Kunle Odunsi
- Lee-Ann H Allen
- Michael B Yaffe
- Mieke C. Brouwer
- Sanjay Ram
- Sora Suzuki
- Stephanie L. Silva-Del Toro
- Steven M. Holland
- Taco W. Kuijpers
- Thejaswini Giridharan
- Tiffany R. Emmons
- Viviana Ferreira
Organizations
- Emma Children’s Hospital
- Harvard Medical School
- Massachusetts Institute of Technology
- National Cancer Institute
- National Institute of Allergy and Infectious Diseases
- National Institutes of Health
- Novartis
- Roswell Park Comprehensive Cancer Center
- Sanquin Research
- United States Department of Defense
- University at Buffalo
- University of Iowa
- University of Massachusetts Medical School
- University of Toledo