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Development and stability of Th17 cells in ovarian cancer requires nitric oxide and endogenous NOS2 activity in cancer-associated CD4+ T cells
  1. Natasa Obermajer1,
  2. Jeffrey L Wong1,
  3. Robert P Edwards4,5,6,
  4. Kong Chen7,
  5. Melanie Scott1,
  6. Shabaana Khader7,
  7. Jay K Kolls7,
  8. Kunle Odunsi8,
  9. Timothy R Billiar1 and
  10. Pawel Kalinski1,2,3
  1. Aff1 grid.21925.3d0000000419369000Department of SurgeryUniversity of Pittsburgh Pittsburgh PA USA
  2. Aff2 grid.21925.3d0000000419369000Department of ImmunologyUniversity of Pittsburgh Pittsburgh PA USA
  3. Aff3 grid.21925.3d0000000419369000Department of Infectious Diseases and MicrobiologyUniversity of Pittsburgh Pittsburgh PA USA
  4. Aff4 grid.460217.60000000403874432Magee-Womens Research Institute Ovarian Cancer Center of Excellence Pittsburgh PA USA
  5. Aff5 Peritoneal/Ovarian Cancer Specialty Care Center Pittsburgh PA USA
  6. Aff6 grid.21925.3d0000000419369000University of Pittsburgh Cancer InstituteUniversity of Pittsburgh Pittsburgh PA USA
  7. Aff7 grid.21925.3d0000000419369000Department of PediatricsUniversity of Pittsburgh School of Medicine Pittsburgh PA USA
  8. Aff8 grid.240614.50000000121818635Departments of Gynecologic Oncology and ImmunologyRoswell Park Cancer Institute Buffalo NY USA

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Meeting abstracts

Th17 cells play reciprocal roles in different forms and at different stages of cancer. We report that the presence of Th17 cells in ovarian cancer ascites correlates with local expression of nitric oxide synthase-2 (NOS2). Furthermore, the development of RORγt+IL-23R+IL-17+ Th17 cells from human naive-, memory- or tumor-infiltrating CD4+ T cells critically depends on NO and endogenous NOS2 induced in CD4+ T cells by Th17-inducing cytokines (IL-1β/IL-6/IL-23) or by cancer-associated IL-1β/IL-6/IL-23/NO-producing MDSCs. Inhibition of NOS2 or its downstream cGMP/cGK signaling pathway abolishes de novo induction of Th17 cells. Moreover, even short-term blockade of NOS/cGMP suppresses the IL-17 production by established Th17 cells isolated from ovarian cancer patients, demonstrating the novel key role of NOS/cGMP in Th17 cell physiology and providing for new therapeutic targets to manipulate Th17- and NOS/cGMP-associated immunity in precancerous lesions and advanced cancer.