Mature neutrophils acquire a T cell suppressor phenotype in the ovarian cancer microenvironment that requires complement and NADPH oxidase activation

Autor: Tiffany Rose Emmons, Kelly L. Singel, ANM Nazmul Khan, Emad Alqassim, Anna Marie Blom, Sanjay Ram, Steven Holland, Kunle Odunsi, Emese Zsiros, Brahm H. Segal
Rok vydání: 2019
Předmět:
Zdroj: The Journal of Immunology. 202:137.13-137.13
ISSN: 1550-6606
0022-1767
DOI: 10.4049/jimmunol.202.supp.137.13
Popis: Metastatic epithelial ovarian cancer (EOC) is associated with ascites and accumulation of immunosuppressive myeloid cells. Granulocytic myeloid-derived suppressor cells are an immature population that impairs anti-tumor immunity. We previously found that granulocytes from the ascites of patients with newly diagnosed EOC were morphologically mature and suppressed ex vivo anti-CD3/CD28-stimulated T cell proliferation. Circulating neutrophils (PMN) from EOC patients were not suppressive, but acquired a suppressor phenotype (defined as ≥ 1 log10 reduction of T cell proliferation) after ascites supernatant exposure. Healthy donor PMN exposed to ascites supernatants acquired the same suppressor phenotype and also inhibited T cell activation and cytokine production. Our goal was to delineate the mechanisms for this PMN suppressor phenotype. Treatment of ascites supernatants with compstatin, an inhibitor of C3 activation, fully abrogated the PMN suppressor phenotype. Inhibition of C5 activation by anti-C5 or OmCI partially abrogated T cell suppression. Neutralizing Ab against C7, a required component of the membrane attack complex had no effect. Malignant effusions from patients with various metastatic cancers also induced the C3-dependent PMN suppressor phenotype, showing generalizability of the phenotype. NADPH oxidase-deficient PMN from patients with X-linked chronic granulomatous disease did not acquire a suppressor phenotype following ascites supernatant exposure, indicating that the suppressor phenotype is NADPH oxidase-dependent. Our results point to PMN impairing T cell expansion and activation in the tumor microenvironment and the potential for targeting C3 and NADPH oxidase as therapeutic approaches.
Databáze: OpenAIRE
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