ArticleThe Journal of experimental medicine2010
Macrophage-dependent nitric oxide expression regulates tumor cell detachment and metastasis after IL-2/anti-CD40 immunotherapy.
Article in The Journal of experimental medicine, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 52 papers.
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Who cites it
52 citing papers in PubMed, 91 citations in OpenAlex.
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- Comparative single cell analysis of wound and cancer identifies the metabolic dialogues between tumor initiating stem cells and macrophages.bioRxiv : the preprint server for biology · 2026Article
- Long-term effects of sub-chronic exposure to L-NAME on reproductive system of male rats.Naunyn-Schmiedeberg's archives of pharmacology · 2025Article
- Harnessing Macrophages in Cancer Therapy: from Immune Modulators to Therapeutic Targets.International journal of biological sciences · 2025Review
- Tumor-associated macrophages in bladder cancer: roles and targeted therapeutic strategies.Frontiers in immunology · 2024Review
- Nanotechnology based gas delivery system: a "green" strategy for cancer diagnosis and treatment.Theranostics · 2024Review
- The Triple Crown: NO, CO, and HPharmacology & therapeutics · 2023Review
- Intralesional TLR4 agonist treatment strengthens the organ defense against colonizing cancer cells in the brain.Oncogene · 2022Article
- Pillars and Gaps of S-Nitrosylation-Dependent Epigenetic Regulation in Physiology and Cancer.Life (Basel, Switzerland) · 2021Review
- Orchestration of myeloid-derived suppressor cells in the tumor microenvironment by ubiquitous cellular protein TCTP released by tumor cells.Nature immunology · 2021Article
- Varied functions of immune checkpoints during cancer metastasis.Cancer immunology, immunotherapy : CII · 2021Review
- Emerging immunotherapies for metastasis.British journal of cancer · 2021Review
- The Role of Nitric Oxide in Cancer: Master Regulator or NOt?International journal of molecular sciences · 2020Review
- Regulatory T cell control of systemic immunity and immunotherapy response in liver metastasis.Science immunology · 2020Article
- Review
- Host cytosolic RNA sensing pathway promotes T Lymphocyte-mediated mycobacterial killing in macrophages.PLoS pathogens · 2020Article
- Nitric Oxide-Releasing Polymeric Materials for Antimicrobial Applications: A Review.Antioxidants (Basel, Switzerland) · 2019Review
- Macrophage polarization as a novel weapon in conditioning tumor microenvironment for bladder cancer: can we turn demons into gods?Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2019Review
- Molecular Mechanisms of Nitric Oxide in Cancer Progression, Signal Transduction, and Metabolism.Antioxidants & redox signaling · 2019Review
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Authors and funding
11 authors at 7 institutions in 1 country.
Funding
Abstract
Using an orthotopic model of renal cell carcinoma, we showed previously that IL-2/anti-CD40 immunotherapy resulted in synergistic anti-tumor responses, whereas IL-2 or α-CD40 alone mediated partial transient anti-tumor effects. We now show that treatment of tumor-bearing mice with IL-2/α-CD40, but not IL-2 or α-CD40, induced significant nitric oxide synthase (NOS) 2 expression in tumor-associated macrophages. In control-treated mice (low NO), NOS2 inhibition reduced tumor burden. However, during immunotherapy (high NO), NOS2 inhibition or macrophage depletion reversed the ability of IL-2/α-CD40 treatment to reduce lung metastases but had no effect on primary tumor burden. Furthermore, IL-2/α-CD40 induced the IFN-γ- and NO-dependent decrease in matrix metalloproteinase (MMP) expression and activity, concomitant with increases in tissue inhibitor of metalloproteinase (TIMP) 1 and E-cadherin expression within tumors. Finally, treatment of tumor-bearing mice with the NO donor JS-K significantly reduced metastases. These data differentiate the mechanism for primary anti-tumor effects of IL-2/α-CD40 immunotherapy, which are independent of NO, from the NO-dependent inhibition of metastases. Furthermore, reduced MMP9 activity implicates M1-polarized macrophages within the tumor microenvironment as critical components of therapeutic response. Our data demonstrate the mechanistic basis for IL-2/α-CD40-mediated control of metastases and suggest that the context-dependent application of NO donors may hold promise for prevention of metastatic disease.
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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.