Mechanism Regulating Reactive Oxygen Species in Tumor-Induced Myeloid-Derived Suppressor Cells1

Myeloid-derived suppressor cells (MDSC) are a major component of the immune suppressive network described in cancer and many other pathological conditions. Recent studies have demonstrated that one of the major mechanisms of MDSC-induced immune suppression is mediated by reactive oxygen species (ROS). However, the mechanism of this phenomenon remained unknown. In this study, we observed a substantial up-regulation of ROS by MDSC in all of seven different tumor models and in patients with head and neck cancer. The increased ROS production by MDSC is mediated by up-regulated activity of NADPH oxidase (NOX2). MDSC from tumor-bearing mice had significantly higher expression of NOX2 subunits, primarily p47phox and gp91phox, compared with immature myeloid cells from tumor-free mice. Expression of NOX2 subunits in MDSC was controlled by the STAT3 transcription factor. In the absence of NOX2 activity, MDSC lost the ability to suppress T cell responses and quickly differentiated into mature macrophages and dendritic cells. These findings expand our fundamental understanding of the biology of MDSC and may also open new opportunities for therapeutic regulation of these cells in cancer.

[1]  D. Mougiakakos,et al.  Naturally occurring regulatory T cells show reduced sensitivity toward oxidative stress-induced cell death. , 2009, Blood.

[2]  D. Mougiakakos,et al.  Transduction with the Antioxidant Enzyme Catalase Protects Human T Cells against Oxidative Stress1 , 2008, The Journal of Immunology.

[3]  P. Dahm,et al.  Reversal of Myeloid Cell–Mediated Immunosuppression in Patients with Metastatic Renal Cell Carcinoma , 2008, Clinical Cancer Research.

[4]  Michelle Collazo,et al.  Subsets of Myeloid-Derived Suppressor Cells in Tumor-Bearing Mice1 , 2008, The Journal of Immunology.

[5]  W. Nacken,et al.  Inhibition of dendritic cell differentiation and accumulation of myeloid-derived suppressor cells in cancer is regulated by S100A9 protein , 2008, The Journal of experimental medicine.

[6]  John D. Lambris,et al.  Modulation of the anti-tumor immune response by complement , 2008, Nature Immunology.

[7]  R. Lai,et al.  Synergistic antitumor effects of CpG oligodeoxynucleotide and STAT3 inhibitory agent JSI‐124 in a mouse melanoma tumor model , 2008, Immunology and cell biology.

[8]  P. De Baetselier,et al.  Identification of discrete tumor-induced myeloid-derived suppressor cell subpopulations with distinct T cell-suppressive activity. , 2008, Blood.

[9]  I. Pollack,et al.  Inhibition of STAT3 Promotes the Efficacy of Adoptive Transfer Therapy Using Type-1 CTLs by Modulation of the Immunological Microenvironment in a Murine Intracranial Glioma1 , 2008, The Journal of Immunology.

[10]  M. Fishman,et al.  Mechanism of all-trans retinoic acid effect on tumor-associated myeloid-derived suppressor cells. , 2007, Cancer research.

[11]  J. Talmadge.  Pathways Mediating the Expansion and Immunosuppressive Activity of Myeloid-Derived Suppressor Cells and Their Relevance to Cancer Therapy , 2007, Clinical Cancer Research.

[12]  K. Gupta,et al.  Altered recognition of antigen is a mechanism of CD8+ T cell tolerance in cancer , 2007, Nature Medicine.

[13]  K. Gupta,et al.  Altered recognition of antigen is a novel mechanism of CD8+ T cell tolerance in cancer , 2007 .

[14]  A. Sica,et al.  Altered macrophage differentiation and immune dysfunction in tumor development. , 2007, The Journal of clinical investigation.

[15]  G. Rabinovich,et al.  Immunosuppressive strategies that are mediated by tumor cells. , 2007, Annual review of immunology.

[16]  D. Gabrilovich,et al.  Targeting of Jak/STAT pathway in antigen presenting cells in cancer. , 2007, Current cancer drug targets.

[17]  T. Assari.  Chronic Granulomatous Disease; fundamental stages in our understanding of CGD , 2006, Medical immunology.

[18]  Ingo Fricke,et al.  All-trans-retinoic acid improves differentiation of myeloid cells and immune response in cancer patients. , 2006, Cancer research.

[19]  D. Gabrilovich,et al.  Role Of Immature Myeloid Cells in Mechanisms of Immune Evasion In Cancer , 2006, Cancer Immunology, Immunotherapy.

[20]  Hua Yu,et al.  Inhibiting Stat3 signaling in the hematopoietic system elicits multicomponent antitumor immunity , 2005, Nature Medicine.

[21]  D. Gabrilovich,et al.  Tumor Associated CD8+ T-Cell Tolerance Induced by Bone Marrow Derived Immature Myeloid Cells , 2005 .

[22]  S. Sebti,et al.  Regulation of dendritic cell differentiation and antitumor immune response in cancer by pharmacologic-selective inhibition of the janus-activated kinase 2/signal transducers and activators of transcription 3 pathway. , 2005, Cancer research.

[23]  D. Gabrilovich,et al.  Tumor-Associated CD8+ T Cell Tolerance Induced by Bone Marrow-Derived Immature Myeloid Cells1 , 2005, The Journal of Immunology.

[24]  Daniele M. Gilkes,et al.  Activation of Dendritic Cells via Inhibition of Jak2/STAT3 Signaling1 , 2005, The Journal of Immunology.

[25]  S. Signoretti,et al.  Arginase-producing myeloid suppressor cells in renal cell carcinoma patients: a mechanism of tumor evasion. , 2005, Cancer research.

[26]  K. Rittinger,et al.  Activation and assembly of the NADPH oxidase: a structural perspective. , 2005, The Biochemical journal.

[27]  P. Sinha,et al.  Reduction of Myeloid-Derived Suppressor Cells and Induction of M1 Macrophages Facilitate the Rejection of Established Metastatic Disease1 , 2005, The Journal of Immunology.

[28]  D. Gabrilovich.  Mechanisms and functional significance of tumour-induced dendritic-cell defects , 2004, Nature Reviews Immunology.

[29]  D. Gabrilovich,et al.  Antigen-Specific Inhibition of CD8+ T Cell Response by Immature Myeloid Cells in Cancer Is Mediated by Reactive Oxygen Species1 , 2004, The Journal of Immunology.

[30]  R. Jove,et al.  Hyperactivation of STAT3 Is Involved in Abnormal Differentiation of Dendritic Cells in Cancer , 2004, The Journal of Immunology.

[31]  D. Gabrilovich,et al.  Inhibition of myeloid cell differentiation in cancer: the role of reactive oxygen species , 2003, Journal of leukocyte biology.

[32]  J. Turkson,et al.  Discovery of JSI-124 (cucurbitacin I), a selective Janus kinase/signal transducer and activator of transcription 3 signaling pathway inhibitor with potent antitumor activity against human and murine cancer cells in mice. , 2003, Cancer research.

[33]  H. Forman,et al.  Redox signaling in macrophages. , 2001, Molecular aspects of medicine.

[34]  Nicholas R. English,et al.  Increased Production of Immature Myeloid Cells in Cancer Patients: A Mechanism of Immunosuppression in Cancer1 , 2001, The Journal of Immunology.

[35]  Richard B. Johnston,et al.  Chronic Granulomatous Disease: Report on a National Registry of 368 Patients , 2000, Medicine.

[36]  J. Darnell,et al.  Stat3 as an Oncogene , 1999, Cell.

[37]  M. Nishimura,et al.  Increased circulating myeloid-derived suppressor cells correlate with clinical cancer stage, metastatic tumor burden, and doxorubicin–cyclophosphamide chemotherapy , 2008, Cancer Immunology, Immunotherapy.

[38]  M. Quinn.  The Neutrophil Respiratory Burst Oxidase , 2005 .

[39]  S. Akira,et al.  Enhanced Th1 activity and development of chronic enterocolitis in mice devoid of Stat3 in macrophages and neutrophils. , 1999, Immunity.