ArticleJournal of immunology (Baltimore, Md. : 1950)2012
Tumor-expressed inducible nitric oxide synthase controls induction of functional myeloid-derived suppressor cells through modulation of vascular endothelial growth factor release.
Article in Journal of immunology (Baltimore, Md. : 1950), 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 93 papers.
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Who cites it
93 citing papers in PubMed, 160 citations in OpenAlex.
- Immune microenvironment modulation unmasks therapeutic benefit of radiotherapy and checkpoint inhibition.Journal for immunotherapy of cancer · 2019Trial
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- Precision Immunotherapeutics for Glioblastoma: Current Approaches and Emerging Strategies in 2026.Cells · 2026Review
- Gasotransmitters bridging tumor biology and immunity: from pathophysiological insights to therapeutic potential.Frontiers in immunology · 2026Review
- Metabolic reprogramming in tumor-associated cells of hematologic malignancies: mechanisms, crosstalk networks, and therapeutic implications in the tumor microenvironment.Frontiers in immunology · 2026Review
- Ferroptosis in Autoimmune Diseases: Research Advances and Therapeutic Strategies.International journal of molecular sciences · 2025Review
- MARCO expression on myeloid-derived suppressor cells is essential for their differentiation and immunosuppression.Cell death discovery · 2025Article
- Epigenetic Regulation of Stromal and Immune Cells and Therapeutic Targets in the Tumor Microenvironment.Biomolecules · 2025Review
- Opposing tumor-cell-intrinsic and -extrinsic roles of the IRF1 transcription factor in antitumor immunity.Cell reports · 2024Article
- NOS2 and COX-2 Co-Expression Promotes Cancer Progression: A Potential Target for Developing Agents to Prevent or Treat Highly Aggressive Breast Cancer.International journal of molecular sciences · 2024Review
- The role of tumor-associated macrophages in tumor immune evasion.Journal of cancer research and clinical oncology · 2024Review
- Myeloid-Derived Suppressor Cells: Therapeutic Target for Gastrointestinal Cancers.International journal of molecular sciences · 2024Review
- Targeting amino acid-metabolizing enzymes for cancer immunotherapy.Frontiers in immunology · 2024Review
- Innovations in Molecular Biomarkers and Biomaterial-Based Immunotherapies for Head & Neck Cancer.Current surgery reports · 2024Review
- Targeting cancer metabolic pathways for improving chemotherapy and immunotherapy.Cancer letters · 2023Review
- The Triple Crown: NO, CO, and HPharmacology & therapeutics · 2023Review
- Inducible nitric oxide synthase (iNOS)-activated Cxcr2 signaling in myeloid cells promotes TGFβ-dependent squamous cell carcinoma lung metastasis.Cancer letters · 2023Article
- Enhancement of Immunotherapies in Head and Neck Cancers Using Biomaterial-Based Treatment Strategies.Tissue engineering. Part C, Methods · 2023Review
- Targeting Nitric Oxide: Say NO to Metastasis.Clinical cancer research : an official journal of the American Association for Cancer Research · 2023Review
- Role of myeloid-derived suppressor cells in tumor recurrence.Cancer metastasis reviews · 2023Review
33 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
13 authors at 5 institutions in 3 countries.
Funding
Abstract
Inducible NO synthase (iNOS) is a hallmark of chronic inflammation that is also overexpressed in melanoma and other cancers. Whereas iNOS is a known effector of myeloid-derived suppressor cell (MDSC)-mediated immunosuppression, its pivotal position at the interface of inflammation and cancer also makes it an attractive candidate regulator of MDSC recruitment. We hypothesized that tumor-expressed iNOS controls MDSC accumulation and acquisition of suppressive activity in melanoma. CD11b(+)GR1(+) MDSC derived from mouse bone marrow cells cultured in the presence of MT-RET-1 mouse melanoma cells or conditioned supernatants expressed STAT3 and reactive oxygen species (ROS) and efficiently suppressed T cell proliferation. Inhibition of tumor-expressed iNOS with the small molecule inhibitor L-NIL blocked accumulation of STAT3/ROS-expressing MDSC, and abolished their suppressive function. Experiments with vascular endothelial growth factor (VEGF)-depleting Ab and recombinant VEGF identified a key role for VEGF in the iNOS-dependent induction of MDSC. These findings were further validated in mice bearing transplantable MT-RET-1 melanoma, in which L-NIL normalized elevated serum VEGF levels; downregulated activated STAT3 and ROS production in MDSC; and reversed tumor-mediated immunosuppression. These beneficial effects were not observed in iNOS knockout mice, suggesting L-NIL acts primarily on tumor- rather than host-expressed iNOS to regulate MDSC function. A significant decrease in tumor growth and a trend toward increased tumor-infiltrating CD8(+) T cells were also observed in MT-RET transgenic mice bearing spontaneous tumors. These data suggest a critical role for tumor-expressed iNOS in the recruitment and induction of functional MDSC by modulation of tumor VEGF secretion and upregulation of STAT3 and ROS in MDSC.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.