Mature neutrophils suppress T cell immunity in ovarian cancer microenvironment
UMass Chan AffiliationsDepartment of Medicine, Division of Infectious Diseases and Immunology
Female Urogenital Diseases and Pregnancy Complications
Hemic and Immune Systems
Immunology and Infectious Disease
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AbstractEpithelial ovarian cancer (EOC) often presents with metastases and ascites. Granulocytic myeloid-derived suppressor cells are an immature population that impairs antitumor immunity. Since suppressive granulocytes in the ascites of patients with newly diagnosed EOC were morphologically mature, we hypothesized that PMN were rendered suppressive in the tumor microenvironment (TME). Circulating PMN from patients were not suppressive but acquired a suppressor phenotype (defined as > /=1 log10 reduction of anti-CD3/CD28-stimulated T cell proliferation) after ascites supernatant exposure. Ascites supernatants (20 of 31 supernatants) recapitulated the suppressor phenotype in PMN from healthy donors. T cell proliferation was restored with ascites removal and restimulation. PMN suppressors also inhibited T cell activation and cytokine production. PMN suppressors completely suppressed proliferation in naive, central memory, and effector memory T cells and in engineered tumor antigen-specific cytotoxic T lymphocytes, while antigen-specific cell lysis was unaffected. Inhibition of complement C3 activation and PMN effector functions, including CR3 signaling, protein synthesis, and vesicular trafficking, abrogated the PMN suppressor phenotype. Moreover, malignant effusions from patients with various metastatic cancers also induced the C3-dependent PMN suppressor phenotype. These results point to PMN impairing T cell expansion and activation in the TME and the potential for complement inhibition to abrogate this barrier to antitumor immunity.
JCI Insight. 2019 Mar 7;4(5). pii: 122311. doi: 10.1172/jci.insight.122311. eCollection 2019 Mar 7. Link to article on publisher's site
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/41007
Full author list omitted for brevity. For the full list of authors, see article.