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Mechanisms Driving Neutrophil-Induced T-cell Immunoparalysis in Ovarian Cancer
Tiffany R Emmons1, Thejaswini Giridharan1, Kelly L Singel1
1Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, New York.
Cancer Immunology Research
|May 15, 2021
Summary
Tumor-associated neutrophils, primed by ascites fluid, suppress T-cell antitumor immunity via complement signaling. This neutrophil-driven immune suppression impairs T-cell function and offers novel immunotherapy targets.
Area of Science:
- Immunology
- Oncology
- Cell Biology
Background:
- T-cell activation in the tumor microenvironment (TME) is crucial for fighting cancer.
- Neutrophils in the TME can suppress T-cell responses through unique mechanisms.
Purpose of the Study:
- To investigate how ascites fluid supernatants (ASC) from ovarian cancer patients affect neutrophil function and immune suppression within the TME.
- To elucidate the mechanisms behind neutrophil-mediated T-cell suppression.
Main Methods:
- Analysis of ovarian cancer ascites fluid supernatants (ASC) on neutrophil function.
- Mass cytometry to characterize neutrophil clusters induced by ASC.
- Assessing complement deposition, NADPH oxidase activation, and phosphatidylserine signaling in neutrophils.
- Evaluating the impact of ASC-activated neutrophils on T-cell proliferation, activation, and function.
Main Results:
- ASC prolonged neutrophil lifespan and induced distinct neutrophil clusters.
- ASC stimulated complement signaling in neutrophils, leading to NADPH oxidase activation.
- ASC-activated neutrophils suppressed tumor-associated T-cells in a complement-dependent manner, causing T-cell immunoparalysis.
- Neutrophil-T cell interactions involved trogocytosis, impairing T-cell signaling pathways (NFAT, IL2, mTOR) and function.
Conclusions:
- Complement-dependent neutrophil activation in the TME creates a distinct form of T-cell nonresponsiveness.
- This neutrophil-driven immune suppression mechanism is a general response to injury and presents potential immunotherapy targets.
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