Mature neutrophils acquire a T cell suppressor phenotype in the ovarian cancer microenvironment characterized by disruption of key T cell signaling and metabolic responses

Autor: Thejaswini Giridharan, Tiffany R Emmons, ANM Nazmul Khan, Sora Suzuki, Aaron Varghese, Meagan Sullivan, Kunle Odunsi, Emese Zsiros, Michael B Yaffe, Brahm H Segal
Rok vydání: 2021
Předmět:
Zdroj: The Journal of Immunology. 206:101.05-101.05
ISSN: 1550-6606
0022-1767
DOI: 10.4049/jimmunol.206.supp.101.05
Popis: Epithelial ovarian cancer (EOC) is the most lethal gynecological cancer. Despite being an immunogenic tumor, single-agent checkpoint inhibitor therapy in the recurrent setting has been disappointing, raising the notion of suppressive factors in the tumor microenvironment (TME) as obstacles to immunotherapy. We previously observed that neutrophils acquire a complement dependent T cell suppressor phenotype in the TME, characterized by inhibition of T cell proliferation and activation through mechanisms distinct from myeloid-derived suppressor cells. Using ascites fluid supernatants (ASC) from patients with EOC as an authentic component of the TME, we identified ASC-activated neutrophils require multiple neutrophil effector functions including NADPH oxidase activation, SNARE-mediated exocytosis and degranulation. ASC-activated neutrophils also adhered to T cells and caused trogocytosis of T cell membranes. These injury and signaling cues resulted in T cell immunoparalysis, characterized by impaired CD3/CD28 stimulated Zap70 phosphorylation, NFAT translocation, IL2 production, glucose uptake, mitochondrial function, and mTOR activation. We also observed that in anti-CD3/CD28 pre-activated T cells, addition of neutrophils + ASC resulted significant reduction in Zap70 phosphorylation. Our results demonstrate complement-dependent priming of neutrophils in the TME inducing a T cell non-responsiveness distinct from established checkpoint pathways and identify targets for immunotherapy. Further studies will focus on the effects of neutrophil suppressors on the TCR signaling cascade and cell stress response pathways that may enable T cell survival in response to neutrophil damage at the expense of activation.
Databáze: OpenAIRE
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