Stat3 Activity in Melanoma Cells Affects Migration of Immune Effector Cells and Nitric Oxide-Mediated Antitumor Effects
Open accessAbstract
Infiltration of immune effector cells in tumors is critical for antitumor immune responses. However, what regulates immune cell infiltration of tumors remains to be identified. Stat3 is constitutively activated with high frequency in diverse cancers, promoting tumor cell growth and survival. Blocking Stat3 signaling in tumors in vivo results in tumor growth inhibition that involves killing of nontransfected tumor cells and infiltration of immune effector cells, suggesting that Stat3 activity in tumor cells might affect immune cell recruitment. However, dying tumor cells can also attract immune cells. In this study, we show in isogenic murine melanomas that natural Stat3 activity is associated with tumor growth and reduction of T cell infiltration. Blocking Stat3 signaling in the melanoma cells containing high Stat3 activity results in expression of multiple chemoattractants, leading to increased migration of lymphocytes, NK cells, neutrophils, and macrophages. In addition, blocking Stat3 triggers tumor cells to produce soluble factors capable of activating macrophage production of NO in vitro and in vivo. TNF-alpha and IFN-beta, which are secreted by Stat3-inhibited tumor cells, are able to activate macrophage NO production, whereas neutralizing TNF-alpha in the tumor supernatant from Stat3-blocked tumor cells abrogates nitrite production. Moreover, interrupting Stat3 signaling in tumor cells leads to macrophage-mediated, nitrite-dependent cytostatic activity against nontrans…
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STAT3 is involved in inflammation-associated carcinogenesis, suppression of the antitumor immune response, and maintenance of cancer stem cells.
“STAT3 is also involved in inflammation-associated carcinogenesis, suppression of the antitumor immune response, and maintenance of cancer stem cells.”
From Critical analysis of the potential for targeting STAT3 in human malignancy (2013) · cites this paper as [96]
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Innate and adaptive immune cells in the tumor microenvironment
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“Inhibition of STAT3 in these tumor cells and also in glioblastoma cell models stimulates secretion of soluble factors, including TNF-α and IFN-β, that ultimately lead to increased infiltration of lymphocytes, natural killer cells, neutrophils, and macrophages, and also activates nitric oxide production from macrophage…”
- Authors
- Burdelya, L., Kujawski, M., Niu, G., Zhong, B., Wang, T., Zhang, S., Kortylewski, M., Shain, K., Kay, H., Djeu, J., Dalton, W., Pardoll, D., Wei, S., & Yu, H.
- Affiliations
- University of South Florida (US)
- Johns Hopkins University (US)
- H. Lee Moffitt Cancer Center and Research Institute and Department of Oncology, College of Medicine, University of South Florida , Tampa, FL 33612
- ORCID
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2005-04-01
- Volume
- 174
- Issue
- 7
- Pages
- 3925-3931
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- PMC
- PMC2632804
- OpenAlex
- W1661698621
- Cited by
- 131
- References
- 3
- Citations by year
- 2025: 1 · 2024: 1 · 2023: 1 · 2022: 2 · 2021: 8 · 2020: 2 · 2019: 4 · 2018: 5 · 2017: 6 · 2016: 4 · 2015: 8 · 2014: 3 · 2013: 15 · 2012: 5
- FWCI
- 6.06
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Cancer Research Institute
- Moffitt Cancer Center
- National Cancer Institute (CA75243, CA89693, R01CA089693, R29CA075243, R01CA140692)
- National Institute of Allergy and Infectious Diseases (AI56213, R01AI056213)
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Keywords
- STAT3 signaling, melanoma, immune cell infiltration, T cell infiltration, macrophage nitric oxide, TNF-α, interferon-beta, chemoattractants, natural killer cells, neutrophils, innate immunity, tumor growth, STAT3 inhibition
- MeSH terms
- Animals, Chemotactic Factors, Chemotaxis, DNA-Binding Proteins, Female, Humans, Immunity, Innate, Macrophages, Melanoma, Experimental, Mice, Inbred Strains, Neoplasm Proteins, Nitric Oxide, T-Lymphocytes, Transfection, Trans-Activators, Mice, Knockout, Cell Line, Tumor, Cell Proliferation, STAT3 Transcription Factor, Mice
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