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

Abstract

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. 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 Mouse breast cancer models were utilized to study the effect of MDSCs on antibody therapy and test the efficacy of combination therapies including a mAb and an MDSC-targeting agent. 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 significantly improved the efficacy of mAb therapy in a mouse model of breast cancer. 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. .

Prognostic role of pretreatment circulating MDSCs in patients with solid malignancies: A meta-analysis of 40 studies

“…This suppression of natural killer cells is cell-cell contact-dependent. [70][71][72][73][74][75][76] Therefore, MDSCs exert a wide range of immunosuppressive functions across the immune systems.…”

Role of the Neutrophil in the Pathogenesis of Advanced Cancer and Impaired Responsiveness to Therapy

“…Other cell types of the innate and adaptive immune systems, which are susceptible to MDSC-mediated suppression of protective functions include natural killer (NK) cells and B cells, and this is also achieved via contact-dependent and -independent mechanisms involving ROS, NO, arginase and TGFβ1 [65,110].…”

NK cells: An attractive candidate for cancer therapy

“…The result of studies demonstrated that MDSCs impair NK cell ADCC function through production of nitric oxide (NO). In addition, the expression of immunosuppressive inhibitory adenosine A2A receptors (A2ARs) by MDSCs in tumor sites signals to inhibit the activity of NK‐cells (Cekic, Day, Sag, & Linden, ; Stiff et al, ). Other study revealed that NK cells attenuated by MDSCs through the inhibiting of IFN‐γ production and NKG2D in glioma cells (Alizadeh et al, ).…”