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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
Inhibiting Stat3 signaling in the hematopoietic system elicits multicomponent antitumor immunity
Kortylewski, M., Kujawski, M., Wang, T., Sheng, W., Zhang, S., Pilon‐Thomas, S., Niu, G., Kay, H. D., Mulé, J. J., Kerr, W. G., et al. (2005) · Nature Medicine · doi:10.1038/nm1325 · Cited by 1,026 · cited 16×
“For treatment using Stat3 inhibitor CPA7 (12, 16), B16 and C4 tumors were”
InfluentialSelf-citationImmunotherapeutic uses of CpG oligodeoxynucleotides
Klinman, D. M. (2004) · Nature reviews. Immunology · doi:10.1038/nri1329 · Cited by 1,007 · cited 2×
“The simplicity of the natural ligands for TLR9, fragments of unmethylated double-stranded DNA, allows for a large-scale synthesis of TLR9 agonists optimized for stability and cell type–specific and species-specific activation (2).”
Cheng, P., Corzo, C. A., Luetteke, N., Yu, B., Nagaraj, S., Bui, M. M., Ortiz, M. L., Nacken, W. K. F., Sorg, C., Vogl, T., et al. (2008) · The Journal of Experimental Medicine · doi:10.1084/jem.20080132 · Cited by 904 · cited 1×
“In addition, as recently shown by Cheng and colleagues (28) and our own studies (12, 29), Stat3 is critical for the”
The BRAF–MAPK signaling pathway is essential for cancer-immune evasion in human melanoma cells
Sumimoto, H., Imabayashi, F., Iwata, T., & Kawakami, Y. (2006) · The Journal of Experimental Medicine · doi:10.1084/jem.20051848 · Cited by 696 · cited 1×
“immunosuppression in the tumor microenvironment by inhibiting the expression of Th1 immunostimulatory molecules and promoting the expression of several immunosuppressive factors (9, 24).”
The use of dendritic cells in cancer immunotherapy
Schuler, G., Schuler‐Thurner, B., & Steinman, R. M. (2003) · Current Opinion in Immunology · doi:10.1016/s0952-7915(03)00015-3 · Cited by 633
Stat3 mediates myeloid cell–dependent tumor angiogenesis in mice
Kujawski, M., Kortylewski, M., Lee, H., Herrmann, A., Kay, H. D., & Yu, H. (2008) · Journal of Clinical Investigation · doi:10.1172/jci35213 · Cited by 594 · cited 2×
“of many factors involved in immunosuppression, tumor invasion, and metastasis in these cells (29).”
Self-citationSano, S., Itami, S., Takeda, K., Tarutani, M., Yamaguchi, Y., Miura, H., Yoshikawa, K., Akira, S., & Takeda, J. (1999) · The EMBO Journal · doi:10.1093/emboj/18.17.4657 · Cited by 519 · cited 1×
“This is consistent with an emerging role for Stat3 in wound healing (30, 31), a physiologic process involving immunosuppression; cell proliferation, invasion, and angiogenesis; and”
Yang, Y., Huang, C.-T., Huang, X., & Pardoll, D. M. (2004) · Nature Immunology · doi:10.1038/ni1059 · Cited by 425 · 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).”
Toll-like receptor 9 (TLR9) agonists in the treatment of cancer
KRIEG, A. M. (2008) · Oncogene · doi:10.1038/sj.onc.1210911 · Cited by 389 · cited 4×
“Whereas TLR9 agonist–based therapies have no major toxicity and show some promise, the efficacy of the TLR9-mediated antitumor immune response is limited, which is largely attributed to the immunosuppression observed in cancer patients (1, 5).”
InfluentialStat3 regulates genes common to both wound healing and cancer
Dauer, D. J., Ferraro, B., Song, L., Yu, B., Mora, L., Buettner, R., Enkemann, S., Jove, R., & Haura, E. B. (2005) · Oncogene · doi:10.1038/sj.onc.1208469 · Cited by 384 · cited 1×
“This is consistent with an emerging role for Stat3 in wound healing (30, 31), a physiologic process involving immunosuppression; cell proliferation, invasion, and angiogenesis; and”
Welte, T., Zhang, S. S. M., Wang, T., Zhang, Z., Hesslein, D. G. T., Yin, Z., Kano, A., Iwamoto, Y., Li, E., Craft, J. E., et al. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0237137100 · Cited by 381
Vicari, A. P., Chiodoni, C., Vaure, C., Aït-Yahia, S., Dercamp, C., Matsos, F., Reynard, O., Taverne, C., Merle, P., Colombo, M. P., et al. (2002) · The Journal of Experimental Medicine · doi:10.1084/jem.20020732 · Cited by 343 · cited 14×
“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).”
InfluentialTrumpfheller, C., Caskey, M., Nchinda, G., Longhi, M. P., Mizenina, O., Huang, Y.-X., Schlesinger, S., Colonna, M., & Steinman, R. (2008) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.0711976105 · Cited by 330 · cited 3×
“of Stat3, whereas poly(I/C), a TLR3 agonist shown to have potent antitumor immunostimulatory effects (20), did not (Fig.”
Crosstalk among Jak-STAT, Toll-like receptor, and ITAM-dependent pathways in macrophage activation
Hu, X., Chen, J., Wang, L., & Ivashkiv, L. B. (2007) · Journal of Leukocyte Biology · doi:10.1189/jlb.1206763 · Cited by 293
Self-citationLee, C.-K., Raz, R., Gimeno, R., Gertner, R., Wistinghausen, B., Takeshita, K., DePinho, R. A., & Levy, D. E. (2002) · Immunity · doi:10.1016/s1074-7613(02)00336-9 · Cited by 242 · cited 1×
“recombinase system has been reported (12, 15).”
Distinct Requirements for IFNs and STAT1 in NK Cell Function
Lee, C., Rao, D. T., Gertner, R., Gimeno, R., Frey, A. B., & Levy, D. E. (2000) · The Journal of Immunology · doi:10.4049/jimmunol.165.7.3571 · Cited by 222 · cited 1×
“Stat1 activation has been shown to be critical for NK antitumor activity (22).”
Dávila, E., Kennedy, R. B., & Celis, E. (2003) · PubMed · Cited by 181
TLR ligand suppression or enhancement of Treg cells? A double-edged sword in immunity to tumours
Conroy, H., Marshall, N. A., & Mills, K. H. G. (2008) · Oncogene · doi:10.1038/sj.onc.1210910 · Cited by 160 · cited 1×
“What has become evident is that TLR agonists, such as CpG oligodeoxynucleotides (ODN), can down-modulate their own activity, which likely represents a physiologic mechanism for limiting collateral damage during infection (14).”
Pallandre, J., Brillard, E., Créhange, G., Radlovic, A., Rémy-Martin, J.-P., Saas, P., Rohrlich, P., Pivot, X. B., Ling, X., Tiberghien, P., et al. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.179.11.7593 · Cited by 159 · cited 1×
“A role of TLR agonists in inducing regulatory T cells in tumors has also been shown, and recent reports indicate a possible function for Stat3 in promoting regulatory T-cell function (27).”
Turkson, J., Zhang, S., Mora, L. B., Burns, A. C., Sebti, S. M., & Jove, R. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m502694200 · Cited by 153 · cited 8×
“For treatment using Stat3 inhibitor CPA7 (12, 16), B16 and C4 tumors were”
InfluentialAppay, V., Jandus, C., Voelter, V., Reynard, S., Coupland, S. E., Rimoldi, D., Líénard, D., Guillaume, P., Krieg, A. Μ., Cerottini, J., et al. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.177.3.1670 · Cited by 152 · cited 1×
“Whereas TLR9 agonist–based therapies have no major toxicity and show some promise, the efficacy of the TLR9-mediated antitumor immune response is limited, which is largely attributed to the immunosuppression observed in cancer patients (1, 5).”
Samarasinghe, R. A., Tailor, P. B., Tamura, T., Kaisho, T., Akira, S., & Ozato, K. (2006) · Journal of Interferon & Cytokine Research · doi:10.1089/jir.2006.26.893 · Cited by 87 · cited 1×
“It has been suggested that CpG can activate IL-10, a known Stat3 activator, through a negative feedback mechanism (18).”
IFN-γ Negatively Regulates CpG-Induced IL-10 in Bone Marrow-Derived Dendritic Cells
Flores, R. R., Diggs, K. A., Tait, L. M., & Morel, P. A. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.178.1.211 · Cited by 27
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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