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Mature neutrophils suppress T cell immunity in ovarian cancer microenvironment

Singel, Kelly L.; Emmons, Tiffany R.; Khan, Anm Nazmul H.; Mayor, Paul C.; Shen, Shichen; Wong, Jerry T.; Morrell, Kayla; Eng, Kevin H.; Mark, Jaron and Bankert, Richard B., et al. (2019) In JCI Insight 4(5).
Abstract

Epithelial 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... (More)

Epithelial 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.

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@article{a6755123-a3de-4cd5-9bbf-1a39f40c0da5,
  abstract     = {<p>Epithelial 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.</p>},
  articleno    = {e122311},
  author       = {Singel, Kelly L. and Emmons, Tiffany R. and Khan, Anm Nazmul H. and Mayor, Paul C. and Shen, Shichen and Wong, Jerry T. and Morrell, Kayla and Eng, Kevin H. and Mark, Jaron and Bankert, Richard B. and Matsuzaki, Junko and Koya, Richard C. and Blom, Anna M. and McLeish, Kenneth R. and Qu, Jun and Ram, Sanjay and Moysich, Kirsten B. and Abrams, Scott I. and Odunsi, Kunle and Zsiros, Emese and Segal, Brahm H.},
  issn         = {2379-3708},
  keyword      = {Complement,Immunology,Neutrophils,Oncology,T cells},
  language     = {eng},
  month        = {02},
  number       = {5},
  publisher    = {The American Society for Clinical Investigation},
  series       = {JCI Insight},
  title        = {Mature neutrophils suppress T cell immunity in ovarian cancer microenvironment},
  url          = {http://dx.doi.org/10.1172/jci.insight.122311},
  volume       = {4},
  year         = {2019},
}