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Nitric Oxide Production by Myeloid-Derived Suppressor Cells Plays a Role in Impairing Fc Receptor–Mediated Natural Killer Cell Function

2018; American Association for Cancer Research; Volume: 24; Issue: 8 Linguagem: Inglês

10.1158/1078-0432.ccr-17-0691

1557-3265

Andrew Stiff, Prashant Trikha, Bethany L. Mundy-Bosse, Elizabeth L. McMichael, Thomas A. Mace, Brooke Benner, Kari Kendra, Amanda R. Campbell, Shalini Gautam, David Abood, Ian Landi, Vincent Hsu, Megan Duggan, Robert Wesolowski, Matthew Old, John H. Howard, Lianbo Yu, Nancy Stasik, Thomas Olencki, Natarajan Muthusamy, Susheela Tridandapani, John C. Byrd, Michael A. Caligiuri, William E. Carson,

Immune Response and Inflammation

Abstract Purpose: mAbs are used to treat solid and hematologic malignancies and work in part through Fc receptors (FcRs) on natural killer cells (NK). However, FcR-mediated functions of NK cells from patients with cancer are significantly impaired. Identifying the mechanisms of this dysfunction and impaired response to mAb therapy could lead to combination therapies and enhance mAb therapy. Experimental Design: Cocultures of autologous NK cells and MDSC from patients with cancer were used to study the effect of myeloid-derived suppressor cells (MDSCs) on NK-cell FcR-mediated functions including antibody-dependent cellular cytotoxicity, cytokine production, and signal transduction in vitro. Mouse breast cancer models were utilized to study the effect of MDSCs on antibody therapy in vivo and test the efficacy of combination therapies including a mAb and an MDSC-targeting agent. Results: MDSCs from patients with cancer were found to significantly inhibit NK-cell FcR-mediated functions including antibody-dependent cellular cytotoxicity, cytokine production, and signal transduction in a contact-independent manner. In addition, adoptive transfer of MDSCs abolished the efficacy of mAb therapy in a mouse model of pancreatic cancer. Inhibition of iNOS restored NK-cell functions and signal transduction. Finally, nonspecific elimination of MDSCs or inhibition of iNOS in vivo significantly improved the efficacy of mAb therapy in a mouse model of breast cancer. Conclusions: MDSCs antagonize NK-cell FcR-mediated function and signal transduction leading to impaired response to mAb therapy in part through nitric oxide production. Thus, elimination of MDSCs or inhibition of nitric oxide production offers a strategy to improve mAb therapy. Clin Cancer Res; 24(8); 1891–904. ©2018 AACR.