The DOI matches its Crossref record; 33 of the 34 references it cites were found in a registry or an index.
Toll-like Receptor 9 Activation of Signal Transducer and Activator of Transcription 3 Constrains Its Agonist-Based Immunotherapy
Open accessPublished version of a preprint
Abstract
Although toll-like receptor (TLR) agonists, such as CpG, are used as immunotherapeutic agents in clinical trials for cancer and infectious diseases, their effects are limited and the underlying mechanism(s) that restrains CpG efficacy remains obscure. Here, we show that signal transducer and activator of transcription 3 (Stat3) plays a key role in down-modulating immunostimulatory effects of CpG. In the absence of interleukin-6 (IL-6) and IL-10 induction, CpG directly activates Stat3 within minutes through TLR9. Ablating Stat3 in hematopoietic cells results in rapid activation of innate immunity by CpG, with enhanced production of IFN-gamma, tumor necrosis factor-alpha, IL-12, and activation of macrophages, neutrophils, and natural killer cells marked with Stat1 activation. Innate immune responses induced by CpG in mice with a Stat3-ablated hematopoietic system cause potent antitumor effects, leading to eradication of large (>1 cm) B16 melanoma tumors within 72 h. Moreover, ablating Stat3 in myeloid cells increases CpG-induced dendritic cell maturation, T-cell activation, generation of tumor antigen-specific T cells, and long-lasting antitumor immunity. A critical role of Stat3 in mediating immunosuppression by certain cytokines and growth factors in the tumor microenvironment has been recently documented. By demonstrating direct and rapid activation of Stat3 by TLR agonists, we identify a second level of Stat3-mediated immunosuppression. Our results further suggest that targeting Stat3 can drastically improve CpG-based immunotherapeutic approaches.
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“In addition to NF-κB activation, TLRs such as TLR2, TLR4, TLR7 and TLR9 activate STAT3 (206, 325).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [206]
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Citations
Cites
Akira, S., & Takeda, K. (2004) · Nature reviews. Immunology · doi:10.1038/nri1391 · Cited by 8,312
The STATs of cancer — new molecular targets come of age
Yu, H., & Jove, R. (2004) · Nature Reviews Cancer · doi:10.1038/nrc1275 · Cited by 2,278 · cited 1×
“IL-10 is frequently overly produced in tumors and is a key activator of signal transducer and activator of transcription 3 (Stat3), which is activated in numerous cancers, promoting expression of diverse molecules important for tumor cell proliferation, survival, invasion, and metastasis (7).”
Self-citationToll Pathway-Dependent Blockade of CD4 + CD25 + T Cell-Mediated Suppression by Dendritic Cells
Pasare, C., & Medzhitov, R. M. (2003) · Science · doi:10.1126/science.1078231 · Cited by 2,000 · cited 1×
“Based on numerous studies in mice demonstrating their efficacy in breaking immune tolerance (3, 4) and promoting Th1-dependent immunity (2), several TLR9 agonists are currently used to treat solid and hematologic malignancies (1).”
Gabrilovich, D. I., Chen, H. L., Girgis, K. R., Cunningham, H. T., Meny, G. M., Nadaf, S., Kavanaugh, D., & Carbone, D. P. (1996) · Nature Medicine · doi:10.1038/nm1096-1096 · Cited by 1,977
Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment
Yu, H., Kortylewski, M., & Pardoll, D. M. (2006) · Nature reviews. Immunology · doi:10.1038/nri1995 · Cited by 1,841 · cited 6×
“Elevated Stat3 activity in tumor stromal immune cells further promotes expression of cytokines and growth factors, including but not limited to IL-10, IL-6, and VEGF, which in turn further activate Stat3 in tumor cells (9, 12, 13).”
InfluentialSelf-citationInducible Gene Targeting in Mice
Kühn, R., Schwenk, F., Aguet, M., & Rajewsky, K. (1995) · Science · doi:10.1126/science.7660125 · Cited by 1,641 · cited 1×
“In the Cre-loxP system, in addition to hematopoietic cells, some organs also undergo partial Stat3 truncation upon poly(I/C) treatment (21).”
STAT3 Mutations in the Hyper-IgE Syndrome
Holland, S. M., DeLeo, F. R., Elloumi, H. Z., Hsu, A. P., Uzel, G., Brodsky, N. N., Freeman, A. F., Demidowich, A. P., Davis, J., Turner, M. L. C., et al. (2007) · New England Journal of Medicine · doi:10.1056/nejmoa073687 · Cited by 1,233 · cited 1×
“Although the potential side effects resulting from Stat3 targeting remain to be fully determined, first insights into possible effects of Stat3 deletion in the human system were revealed in patients with hyper-IgE syndrome (32, 33).”
Takeda, K., Clausen, B. E., Kaisho, T., Tsujimura, T., Terada, N., Förster, I., & Akira, S. (1999) · Immunity · doi:10.1016/s1074-7613(00)80005-9 · Cited by 1,220
Regulation of the innate and adaptive immune responses by Stat-3 signaling in tumor cells
Wang, T., Niu, G., Kortylewski, M., Burdelya, L. G., Shain, K. H., Zhang, S., Bhattacharya, R., Gabrilovich, D. I., Heller, R. F., Coppola, D., et al. (2003) · Nature Medicine · doi:10.1038/nm976 · Cited by 1,182 · cited 5×
“Elevated Stat3 activity in tumor stromal immune cells further promotes expression of cytokines and growth factors, including but not limited to IL-10, IL-6, and VEGF, which in turn further activate Stat3 in tumor cells (9, 12, 13).”
InfluentialSelf-citationDominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome
Minegishi, Y., Saitō, M., Tsuchiya, S., Tsuge, I., Takada, H., Hara, T., Kawamura, N., Ariga, T., Pašić, S., Stojković, O., et al. (2007) · Nature · doi:10.1038/nature06096 · Cited by 1,075
Cited by
Sorted by citations
STATs in cancer inflammation and immunity: a leading role for STAT3
Yu, H., Pardoll, D., & Jove, R. (2009) · Nature reviews. Cancer · doi:10.1038/nrc2734 · Cited by 4,383
“Lipopolysaccharide is known to function through Toll-like receptor 4 ( TLR4 ), and it has been shown that the engagement of TLR4 and TLR9 can also directly activate STAT3 (Ref”
Self-citationRevisiting STAT3 signalling in cancer: new and unexpected biological functions
Yu, H., Lee, H., Herrmann, A., Buettner, R., & Jove, R. (2014) · Nature Reviews Cancer · doi:10.1038/nrc3818 · Cited by 2,137
Self-citationIL-6 in inflammation, autoimmunity and cancer
Hirano, T. (2021) · International Immunology · doi:10.1093/intimm/dxaa078 · Cited by 1,453
“In addition to NF-κ B activation, TLRs such as TLR2, TLR4, TLR7 and TLR9 activate STAT3 (206, 325).”
BackgroundGlioma cancer stem cells induce immunosuppressive macrophages/microglia
Wu, A., Wei, J., Kong, L.-Y., Wang, Y., Priebe, W., Qiao, W., Sawaya, R. A., & Heimberger, A. B. (2010) · Neuro-Oncology · doi:10.1093/neuonc/noq082 · Cited by 705
Aptamer-based targeted therapy
Zhu, G., & Chen, X. (2018) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2018.08.005 · Cited by 522
Metadata
- Authors
- Kortylewski, M., Kujawski, M., Herrmann, A., Yang, C., Wang, L., Liu, Y., Salcedo, R., & Yu, H.
- Affiliations
- City Of Hope National Medical Center (US)
- National Cancer Institute (US)
- Venue
- Cancer Research
- Published
- 2009-03-15
- Volume
- 69
- Issue
- 6
- Pages
- 2497-2505
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC2657819
- OpenAlex
- W2137285200
- Cited by
- 122
- References
- 34
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 5 · 2023: 7 · 2022: 5 · 2021: 5 · 2020: 9 · 2019: 5 · 2018: 12 · 2017: 8 · 2016: 7 · 2015: 5 · 2014: 5 · 2013: 9 · 2012: 9
- FWCI
- 5.83
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (R01CA122976)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- TLR9, STAT3, CpG oligodeoxynucleotides, immunosuppression, innate immunity, dendritic cell maturation, antitumor immunity, melanoma, myeloid cells, tumor microenvironment, cytokines
- MeSH terms
- Animals, Dendritic Cells, Immunotherapy, Male, Melanoma, Experimental, Mice, Inbred C3H, Mice, Inbred C57BL, Cytokines, Th1 Cells, CpG Islands, Chemokines, STAT3 Transcription Factor, Toll-Like Receptor 9, Mice
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