Mechanisms Driving Neutrophil-Induced T-cell Immunoparalysis in Ovarian Cancer
UMass Chan AffiliationsDivision of Infectious Diseases and Immunology, Department of Medicine
Document TypeJournal Article
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AbstractT-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.
Emmons TR, Giridharan T, Singel KL, Khan ANH, Ricciuti J, Howard K, Silva-Del Toro SL, Debreceni IL, Aarts CEM, Brouwer MC, Suzuki S, Kuijpers TW, Jongerius I, Allen LH, Ferreira VP, Schubart A, Sellner H, Eder J, Holland SM, Ram S, Lederer JA, Eng KH, Moysich KB, Odunsi K, Yaffe MB, Zsiros E, Segal BH. Mechanisms Driving Neutrophil-Induced T-cell Immunoparalysis in Ovarian Cancer. Cancer Immunol Res. 2021 Jul;9(7):790-810. doi: 10.1158/2326-6066.CIR-20-0922. Epub 2021 May 14. PMID: 33990375; PMCID: PMC8287091. Link to article on publisher's site
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/42021
Full author list omitted for brevity. For the full list of authors, see article.