Stiff et al. found that nitric oxide production by MDSCs impairs the FcR-mediated signal transduction and downstream effector functions (cellular cytotoxicity, antibody-dependent cell-mediated cytotoxicity, and cytokine production) in NK cells of mice and humans, thus antagonizing NK cell-dependent monoclonal antibody (mAb) therapies. Depletion of MDSCs or inhibition of iNOS (a nitric oxide-producing enzyme) in vivo restored NK cell functions and improved the efficacy of mAb therapies in mouse models.
PURPOSE: Monoclonal antibodies (mAb) are used to treat solid and hematological malignancies, and work in part through Fc receptors (FcR) on natural killer cells (NK). However, FcR mediated functions of NK cells from cancer patients 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: Co-cultures of autologous NK cells and MDSC from cancer patients were used to study the effect of MDSC 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 MDSC on antibody therapy in vivo and test the efficacy of combination therapies including a mAb and a MDSC targeting agent. Results: Cancer patient MDSC were found to significantly inhibit NK cell FcR mediated functions including ADCC, cytokine production, and signal transduction in a contact independent manner. In addition, adoptive transfer of MDSC abolished the efficacy of mAb therapy in a mouse model of pancreatic cancer. Inhibition of iNOS restored NK cell functions and signal transduction. Finally, non-specific elimination of MDSC or inhibition of iNOS in vivo significantly improved the efficacy of mAb therapy in a mouse model of breast cancer. CONCLUSIONS: MDSC 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 MDSC or inhibition of nitric oxide production offers a strategy to improve mAb therapy.
Author Info: (1) Medical Scientist Training Program, Ohio State University. (2) Center for Childhood Cancer, Nationwide Children's Hospital. (3) Arthur G. James Comprehensive Cancer Center and
Author Info: (1) Medical Scientist Training Program, Ohio State University. (2) Center for Childhood Cancer, Nationwide Children's Hospital. (3) Arthur G. James Comprehensive Cancer Center and Solove Research Institute, Ohio State University. (4) Department of Immunology, University of Pittsburgh. (5) Department of Internal Medicine, Division of Medical Oncology, The Ohio State University Medical Center. (6) Comprehensive Cancer Center, Ohio State University Wexner Medical Center. (7) Division of Internal Medicine, Ohio State University. (8) Ohio State University. (9) Microbiology, Texas Biomedical Research Institute. (10) Comprehensive Cancer Center, Ohio State University Wexner Medical Center. (11) Oncological Sciences, Mount Sinai Medical Center. (12) Ohio State University. (13) Comprehensive Cancer Center, Ohio State University. (14) Internal Medicine/Div. of Medical Oncology, Ohio State University Comprehensive Cancer Center. (15) Department of Otolaryngology, Ohio State University. (16) Ohio State University. (17) Center for Biostatistics, Ohio State University. (18) Ohio State University. (19) Medical Oncology, Ohio State University. (20) Division of Hematology, Department of Internal Medicine and Comprehensive Cancer Center, Ohio State University. (21) Ohio State University. (22) Division of Hematology, Ohio State University. (23) Comprehensive Cancer Center, Ohio State University. (24) Department of Surgery, Ohio State University william.carson@osumc.edu.
