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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
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
Targeting the Interleukin-6/Jak/Stat Pathway in Human Malignancies
Sansone, P., & Bromberg, J. (2012) · Journal of Clinical Oncology · doi:10.1200/jco.2010.31.8907 · Cited by 518
“5), underscoring its role in early development, whereas tissue-specific loss of Stat3 demonstrates its importance in regulating inflammation (Th17 cells, myeloid cells, Bregs, dendritic cells).(33,53-60)”
BackgroundKortylewski, M., Swiderski, P. M., Herrmann, A., Wang, L., Kowolik, C. M., Kujawski, M., Lee, H., Scuto, A., Liu, Y., Yang, C., et al. (2009) · Nature Biotechnology · doi:10.1038/nbt.1564 · Cited by 384
Self-citationThe role of STAT3 in leading the crosstalk between human cancers and the immune system
Wang, Y., Shen, Y., Wang, S., Shen, Q., & Zhou, X. (2017) · Cancer Letters · doi:10.1016/j.canlet.2017.12.003 · Cited by 343
STAT3, stem cells, cancer stem cells and p63
Galoczová, M., Coates, P. J., & Vojtěšek, B. (2018) · Cellular & Molecular Biology Letters · doi:10.1186/s11658-018-0078-0 · Cited by 272
“Recent studies also identified Toll-like receptors as Tyr705 activators [44, 45].”
Zhu, G., Mei, L., Vishwasrao, H. D., Jacobson, O., Wang, Z., Liu, Y., Yung, B. C., Fu, X., Jin, A. J., Niu, G., et al. (2017) · Nature Communications · doi:10.1038/s41467-017-01386-7 · Cited by 257
Self-citationS1PR1-STAT3 Signaling Is Crucial for Myeloid Cell Colonization at Future Metastatic Sites
Deng, J., Liu, Y., Lee, H., Herrmann, A., Zhang, W., Zhang, C., Shen, S., Priceman, S. J., Kujawski, M., Pal, S. K., et al. (2012) · Cancer Cell · doi:10.1016/j.ccr.2012.03.039 · Cited by 254
“CpG is a small oligonucleotide with methylated CpG dinucleotides that activate Tolllike receptor (TLR)-9, which is mainly expressed in the endosomal compartment of myeloid and B cells (Kortylewski et al., 2009b).”
InfluentialSelf-citationMultiple regulation pathways and pivotal biological functions of STAT3 in cancer
Yuan, J., Zhang, F., & Niu, R. (2015) · Scientific Reports · doi:10.1038/srep17663 · Cited by 235
Rébé, C., Végran, F., Berger, H., & Ghiringhelli, F. (2013) · JAK-STAT · doi:10.4161/jkst.23010 · Cited by 222
Imageable Antigen‐Presenting Gold Nanoparticle Vaccines for Effective Cancer Immunotherapy In Vivo
Lee, I., Kwon, H., An, S., Kim, D., Kim, S., Yu, M. K., Lee, J., Lee, T. S., Im, S., & Jon, S. (2012) · Angewandte Chemie International Edition · doi:10.1002/anie.201203193 · Cited by 195
Glioma Stem Cells: Signaling, Microenvironment, and Therapy
Liebelt, B. D., Shingu, T., Zhou, X., Ren, J., Shin, S., & HU, J. L. (2016) · Stem Cells International · doi:10.1155/2016/7849890 · Cited by 200
Heterogeneous Responses of Hematopoietic Stem Cells to Inflammatory Stimuli Are Altered with Age
Mann, M., Mehta, A., de Boer, C. G., Kowalczyk, M. S., Lee, K., Haldeman, P., Rogel, N., Knecht, A. R., Farouq, D., Regev, A., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.11.056 · Cited by 188
Hossain, D. M. S., Pal, S. K., Moreira, D., Duttagupta, P. A., Zhang, Q., Won, H., Jones, J. O., D’Apuzzo, M., Forman, S. J., & Kortylewski, M. (2015) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-14-3145 · Cited by 192
“The outcome of TLR9 signaling seems to be defined by a multilayered negative feedback regulation through STAT3 (41, 46).”
Self-citationSzebeni, G. J., Vízler, C., Kitajka, K., & Puskás, L. G. (2017) · Mediators of Inflammation · doi:10.1155/2017/9294018 · Cited by 195
STAT3 Negatively Regulates Type I IFN-Mediated Antiviral Response
Wang, W., Levy, D. E., & Lee, C. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1004128 · Cited by 179
Lu, Y., Yang, Y., Gu, Z., Zhang, J., Song, H., Xiang, G., & Yu, C. (2018) · Biomaterials · doi:10.1016/j.biomaterials.2018.05.025 · Cited by 173
STAT3: An Emerging Therapeutic Target for Hepatocellular Carcinoma
Lee, C., & Cheung, S. (2019) · Cancers · doi:10.3390/cancers11111646 · Cited by 148
“STAT3 is primarily activated by ligand binding to (i) cytokine receptors and (ii) growth factor receptors, (iii) toll-like receptors (TLRs) [30], (iv) G-protein coupled receptors (GPCRs) [31] and (v) cytoplasmic tyrosine kinases such as Src and Abl [32,33] (Figure 1).”
BackgroundSTAT3: A Target to Enhance Antitumor Immune Response
Lee, H., Pal, S. K., Reckamp, K. L., Figlin, R. A., & Yu, H. (2010) · Current topics in microbiology and immunology · doi:10.1007/82_2010_51 · Cited by 138
“Furthermore, conjugation of CpG to siRNA targeting Stat3 activates various populations of immune cells including DCs and macrophages and ultimately induces robust anti-tumor immune responses (Kortylewski et al. 2009b).”
BackgroundInfluentialSelf-citationHerrmann, A., Kortylewski, M., Kujawski, M., Zhang, C., Reckamp, K. L., Armstrong, B., Wang, L. Q., Kowolik, C. M., Deng, J., Figlin, R. A., et al. (2010) · Cancer Research · doi:10.1158/0008-5472.can-10-0736 · Cited by 135
“Related to this observation, it has been reported that CpG can activate Stat3, constraining antitumor immune responses (24, 36, 37).”
BackgroundSelf-citationSTAT3, a master regulator of anti-tumor immune response
Rébé, C., & Ghiringhelli, F. (2019) · Cancers · doi:10.3390/cancers11091280 · Cited by 129
Toll-like receptors and toll-like receptor-targeted immunotherapy against glioma
Xun, Y., Yang, H., Kaminska, B., & You, H. (2021) · Journal of Hematology & Oncology · doi:10.1186/s13045-021-01191-2 · Cited by 129
“LPS-mediated TLR4 signaling was also associated with immune phenotype transition in GBM cells and GSCs to induce antitumoral effect, leading to better survival in a cohort of patients with GBM [152].”
BackgroundInfluentialSTAT3 in Tumor-Associated Myeloid Cells: Multitasking to Disrupt Immunity
Su, Y., Banerjee, S., White, S. V., & Kortylewski, M. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19061803 · Cited by 125
Self-citationTargeting tumor-associated macrophages for cancer immunotherapy
Shu, Y., & Cheng, P. (2020) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2020.188434 · Cited by 122
Alshamsan, A., Hamdy, S. I., Samuel, J., El‐Kadi, A. O. S., Lavasanifar, A., & Uludağ, H. (2009) · Biomaterials · doi:10.1016/j.biomaterials.2009.11.003 · Cited by 114
Chirasani, S. R., Leukel, P., Gottfried, E., Hochrein, J., Stadler, K., Neumann, B. H., Oefner, P. J., Gronwald, W., Bogdahn, U., Hau, P., et al. (2012) · International Journal of Cancer · doi:10.1002/ijc.27712 · Cited by 112
TLR9-mediated siRNA delivery for targeting of normal and malignant human hematopoietic cells in vivo
Zhang, Q., Hossain, D. M. S., Nechaev, S., Kozłowska, A. K., Zhang, W., Liu, Y., Kowolik, C. M., Swiderski, P. M., Rossi, J. J., Forman, S. J., et al. (2013) · Blood · doi:10.1182/blood-2012-07-442590 · Cited by 107
Self-citationLeukemia cell–targeted STAT3 silencing and TLR9 triggering generate systemic antitumor immunity
Hossain, D. M. S., Santos, C. D., Zhang, Q., Kozłowska, A. K., Liu, H., Gao, C., Moreira, D., Swiderski, P. M., Jozwiak, A. A., Kline, J. P., et al. (2013) · Blood · doi:10.1182/blood-2013-07-517987 · Cited by 103
Self-citationThe revival of CpG oligonucleotide-based cancer immunotherapies
Adamus, T., & Kortylewski, M. (2018) · Współczesna Onkologia · doi:10.5114/wo.2018.73887 · Cited by 100
“These therapeutic effects resulted from an unleashed innate and adaptive antitumor immunity without any indication of autoimmune disorders within the treatment window [42].”
BackgroundSelf-citationZhang, Q., Hossain, D. M. S., Duttagupta, P. A., Moreira, D., Zhao, X., Won, H., Buettner, R., Nechaev, S., Majka, M., Zhang, B., et al. (2016) · Blood · doi:10.1182/blood-2015-08-665604 · Cited by 90
“This was likely a result of CpG/TLR9-induced autocrine expression of IL-6 and/or IL-10.(29,30) Consistentwith other reports,(26,27) the STAT3 decoy sequence also reduces DNA binding of a closely related transcription factor, STAT1 (Figure 2A).”
BackgroundSelf-citationTLR9 Signaling in the Tumor Microenvironment Initiates Cancer Recurrence after Radiotherapy
Gao, C., Kozłowska, A. K., Nechaev, S., Li, H., Zhang, Q., Hossain, D. M. S., Kowolik, C. M., Chu, P. G., Swiderski, P. M., Diamond, D. J., et al. (2013) · Cancer Research · doi:10.1158/0008-5472.can-13-1314 · Cited by 89
Self-citationMcGarry, T., Hanlon, M. M., Marzaioli, V., Cunningham, C. C., Krishna, V., Murray, K., Hurson, C. J., Gallagher, P., Nagpal, S., Veale, D. J., et al. (2021) · Clinical & Translational Immunology · doi:10.1002/cti2.1237 · Cited by 89
Neutrophils, a candidate biomarker and target for radiation therapy?
Schernberg, A., Blanchard, P., Chargari, C., & Deutsch, É. (2017) · Acta Oncologica · doi:10.1080/0284186x.2017.1348623 · Cited by 80
“Ablating STAT3 in hematopoietic cells has been associated with activation of innate immunity by TLRs, with enhanced production of IFN-c, TNF-a, IL-12, activation of neutrophils, and enlarged antitumor activity [38].”
BackgroundMoreira, D., Adamus, T., Zhao, X., Su, Y.-L., Zhang, Z., White, S. V., Swiderski, P., Lu, X., DePinho, R. A., Pal, S. K., et al. (2018) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-18-1277 · Cited by 80
“This observation corresponds to our original findings of increased neutrophil activity in mice with hematopoietic cell–selective Stat3 ablation, especially in response to local TLR9 stimulation (48, 49).”
ResultSelf-citationAlizadeh, D., Zhang, L., Brown, C. E., Farrukh, O., Jensen, M. C., & Badie, B. (2010) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-09-3087 · Cited by 78
“Effect of CpG-ODN on immunosuppressive cells Because previous reports have linked CpG-ODN to an increase in immunosuppressive cells (20), we next evaluated the effect of the number of CpG-ODN injections on regulatory T cells (Treg; CD4CD25FOXP3) and myeloid-derived suppressor cells (MDSC; CD11bGr-1).”
BackgroundResultParakh, S., Ernst, M., & Poh, A. R. (2021) · Cancers · doi:10.3390/cancers13246228 · Cited by 77
“Tregs—Tregs are a subset of CD4 T-cells that sustain an immunosuppressive tumor microenvironment via secretion of IL10 and TGFβ [127,128].”
InfluentialDendritic Cell-Based Cancer Gene Therapy
Smits, E., Anguille, S., Cools, N., Berneman, Z. N., & Tendeloo, V. F. V. (2009) · Human Gene Therapy · doi:10.1089/hum.2009.145 · Cited by 75
Activation of STAT3 is a key event in TLR4 signaling-mediated melanoma progression
Fu, X., Liu, B., Wang, Y., Li, J., Zhu, P., Li, T., Tse, A. K., Chou, J., Yin, C., Bai, J., et al. (2020) · Cell Death and Disease · doi:10.1038/s41419-020-2440-1 · Cited by 73
Self-citationNgamcherdtrakul, W., Reda, M. M., Nelson, M. A., Wang, R., Zaidan, H. Y., Bejan, D. S., Hoang, N. H., Lane, R. S., Luoh, S., Leachman, S. A., et al. (2021) · Advanced Materials · doi:10.1002/adma.202100628 · Cited by 71
Stephen, Z. R., & Zhang, M. (2020) · Advanced Healthcare Materials · doi:10.1002/adhm.202001415 · Cited by 70
TLR9 Is Critical for Glioma Stem Cell Maintenance and Targeting
Herrmann, A., Cherryholmes, G. A., Schroeder, A., Phallen, J. A., Alizadeh, D., Xin, H., Wang, T., Lee, H., Lahtz, C., Swiderski, P. M., et al. (2014) · Cancer Research · doi:10.1158/0008-5472.can-14-1151 · Cited by 72
Self-citationTh1 cytokine-based immunotherapy for cancer
Xu, H. (2014) · Hepatobiliary & pancreatic diseases international · doi:10.1016/s1499-3872(14)60305-2 · Cited by 67
Myeloid cells as a target for oligonucleotide therapeutics: turning obstacles into opportunities
Kortylewski, M., & Moreira, D. (2017) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-017-1966-2 · Cited by 66
Self-citationMoreira, D., Zhang, Q., Hossain, D. M. S., Nechaev, S., Li, H., Kowolik, C. M., D’Apuzzo, M., Forman, S. J., Jones, J. O., Pal, S. K., et al. (2015) · Oncotarget · doi:10.18632/oncotarget.4029 · Cited by 62
“STAT3 is an essential negative feedback inhibitor for TLR9 signaling which is activated by NF-κB-induced cytokines such as IL-6 or IL-10 [9, 13, 14].”
BackgroundSelf-citationYun, H.-M., Oh, J., Shim, J.-H., Ban, J. O., Park, K.-R., Kim, J.-H., Lee, D., Kang, J.-W., Park, Y. H., Yu, D., et al. (2013) · Cell Death and Disease · doi:10.1038/cddis.2013.166 · Cited by 59
“In agreement with these observations, in a previous study, ablating STAT3 was found to activatemacrophages, NK cells, and neutrophils, and have an antitumor effect.(50) It is well known that inactivation of STAT3 is required for IL-10-mediated immunosuppressive signaling.”
ResultLycopene Protects Against Spontaneous Ovarian Cancer Formation in Laying Hens
Şahin, K., Yenice, E., Tuzcu, M., Orhan, C., Mızrak, C., Özercan, İ. H., Şahin, N., Yılmaz, B., Bilir, B., Özpolat, B., et al. (2018) · Journal of Cancer Prevention · doi:10.15430/jcp.2018.23.1.25 · Cited by 54
Hashimoto, S., Hashimoto, A., Muromoto, R., Kitai, Y., Oritani, K., & Matsuda, T. (2022) · Cells · doi:10.3390/cells11162618 · Cited by 51
Khairuddin, N., Gantier, M. P., Blake, S. J., Wu, S. Y., Behlke, M. A., Williams, B. R. G., & McMillan, N. A. J. (2011) · Immunology and Cell Biology · doi:10.1038/icb.2011.19 · Cited by 48
Targeting STAT3 in Cancer with Nucleotide Therapeutics
Lau, Y.-T. K., Ramaiyer, M. S., Johnson, D. E., & Grandis, J. R. (2019) · Cancers · doi:10.3390/cancers11111681 · Cited by 49
“Therefore, to generate a sufficient immune response, it is necessary to both stimulate TLR9 and deactivate STAT3 [76,77].”
BackgroundMolavi, O., Mahmud, A., Hamdy, S. I., Hung, R., Lai, R. L., Samuel, J., & Lavasanifar, A. (2009) · Molecular Pharmaceutics · doi:10.1021/mp900145g · Cited by 47
Kozłowska, A. K., Florczak, A., Smialek, M. J., Dondajewska, E., Mackiewicz, A. A., Kortylewski, M., & Dams‐Kozlowska, H. (2017) · Acta Biomaterialia · doi:10.1016/j.actbio.2017.07.014 · Cited by 43
Self-citationGonzález-Ávila, G., Sommer, B., Flores‐Soto, E., & Aquino‐Gálvez, A. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms242316887 · Cited by 44
“Moreover, agonist activation of TRL9 can stimulate the STAT-3 signaling pathway in mouse B16 melanoma cells, which, in turn, can activate MMPs’ transcription, such as MMP-9 [22].”
BackgroundLu, Y., Wang, Y., Miao, L., Haynes, M. T., Xiang, G., & Huang, L. (2016) · Cancer Letters · doi:10.1016/j.canlet.2016.05.025 · Cited by 43
Targeting the Innate Immune System as Immunotherapy for Acute Myeloid Leukemia
Curran, E. K., Corrales, L. P., & Kline, J. P. (2015) · Frontiers in Oncology · doi:10.3389/fonc.2015.00083 · Cited by 41
“STAT3 activity has also been found to hamper the effect of locally administered TLR9 ligands (67).”
Backgroundvan de Ven, R., Lindenberg, J. J., Oosterhoff, D., & de Gruijl, T. D. (2013) · Frontiers in Immunology · doi:10.3389/fimmu.2013.00403 · Cited by 39
“Indeed, evidence for the therapeutic efficacy of combined STAT3 inhibition and CpG ODN was previously provided by Kortylewski and colleagues, showing superior immune stimulatory effects of CpG by eliminating collateral STAT3-mediated suppressive effects (62, 63).”
BackgroundSTAT3 plays an important role in DNA replication by turning on WDHD1
Zhou, Y., & Chen, J. J. (2021) · Cell & Bioscience · doi:10.1186/s13578-020-00524-x · Cited by 38
“Toll-like receptors (TLRs) and microRNAs were recently identified to regulate JAK-STAT signaling in cancer [3, 20, 21].”
BackgroundSorrentino, R., Morello, S., Luciano, A., Crother, T. R., Maiolino, P., Bonavita, E., Arra, C., Adcock, I. M., Arditi, M., & Pinto, A. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.1000881 · Cited by 37
“TNF-a, IL-6, IL-12p40, IL-10, IFN-a, IFN-g, IL-17A, and IgG2b were measured in homogenate and BAL by using commercially available ELISAs (R&D Systems and eBioscience, London, U.K.; Bethyl Laboratories, Montgomery, TX).”
BackgroundResultInfluentialAptamers: A Feasible Technology in Cancer Immunotherapy
Soldevilla, M. M., Villanueva, H., & Pastor, F. (2016) · Journal of Immunology Research · doi:10.1155/2016/1083738 · Cited by 37
“This targeted inhibition leads to activation of tumor-associated immune cells and strong antitumor immune responses [75, 76].”
Harnessing DNA-induced immune responses for improving cancer vaccines
Herrada, A. A., Rojas-Colonelli, N., González-Figueroa, P., Roco, J. A., Oyarce, C., Ligtenberg, M. A., & Lladser, Á. (2012) · Human Vaccines & Immunotherapeutics · doi:10.4161/hv.22345 · Cited by 37
Yan, J., Wang, Z., Yang, H.-Z., Liu, H.-Z., Mi, S., Lv, X.-X., Fu, X.-M., Yan, H.-M., Zhang, X.-W., Zhan, Q., et al. (2011) · PLoS ONE · doi:10.1371/journal.pone.0024705 · Cited by 36
Özcan, E., Rauter, I., Garibyan, L., Dillon, S. R., & Geha, R. S. (2011) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2011.04.052 · Cited by 35
Co-evolution of glioma and immune microenvironment
Elguindy, M. M., Young, J. S., Ho, W. S., & Lu, R. O. (2024) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2024-009175 · Cited by 39
“52 Regulatory T cells (Tregs) can also induce the expression of stemness-related genes (eg, CD133, SOX2, NESTIN) by secreting TGF-β that promote NF-kB or STAT3 signaling pathway.”
Influentialvan den Hout, M. F. C. M., Sluijter, B. J. R., Santegoets, S. J. A. M., van Leeuwen, P. A. M., van den Tol, M. P., van den Eertwegh, A. J. M., Scheper, R. J., & de Gruijl, T. D. (2016) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-016-1811-z · Cited by 34
B Cell Lymphoma Immunotherapy Using TLR9-Targeted Oligonucleotide STAT3 Inhibitors
Zhao, X., Zhang, Z., Moreira, D., Su, Y., Won, H., Adamus, T., Dong, Z., Liang, Y., Yin, H. H., Swiderski, P. M., et al. (2018) · Molecular Therapy · doi:10.1016/j.ymthe.2018.01.007 · Cited by 32
“Our previous studies and current observations suggest that blocking STAT3 removes restraints on the potency of TLR9-driven immunostimulation.(26,28,38,49) This is in agreement with an original report inmouse lymphoma cells that suggested the role of STAT3 in restricting BCL cell immunogenicity.”
ResultSelf-citationImageable Antigen‐Presenting Gold Nanoparticle Vaccines for Effective Cancer Immunotherapy In Vivo
Lee, I., Kwon, H., An, S., Kim, D., Kim, S., Yu, M. K., Lee, J., Lee, T. S., Im, S., & Jon, S. (2012) · Angewandte Chemie · doi:10.1002/ange.201203193 · Cited by 31
Dual functions of STAT3 in LPS-induced angiogenesis of hepatocellular carcinoma
Wang, Z., Yan, M., Li, J., Long, J., Li, Y., & Zhang, H. (2018) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2018.11.016 · Cited by 25
Xing, W.-Y., Zhang, Z., Xu, S., Hong, Q., Tian, Q.-X., Ye, Q., Wang, H., Yu, D., Xu, D., & Xie, D. (2020) · International Immunopharmacology · doi:10.1016/j.intimp.2020.106346 · Cited by 25
Mojiri-Forushani, H., Khajehali, E., Adelipour, M., & Mohammadi, A. (2022) · Molecular Biology Reports · doi:10.1007/s11033-022-08219-x · Cited by 24
“It has been reported that involvement of TLR4 and TLR9 can also stimulate STAT3 [40].”
BackgroundThe proprotein convertase PC1/3 regulates TLR9 trafficking and the associated signaling pathways
Duhamel, M., Rodet, F., Murgoci, A., Desjardins, R., Gagnon, H., Wisztorski, M., Fournier, I., Day, R. W., & Salzet, M. (2016) · Scientific Reports · doi:10.1038/srep19360 · Cited by 18
“Because TLR9, NF-κ B and STAT3 are key molecules involved in tumor propagation 20,21 , con-trol of their activation by PC1/3 represents a promising and potent antitumoral therapy.”
Influentialvan Pul, K. M., Vuylsteke, R. J. C. L. M., de Beijer, M. T. A., van de Ven, R., van den Tol, M. P., Stockmann, H. B. A. C., & de Gruijl, T. D. (2020) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2020-000761 · Cited by 19
Alcantara, M. B., Tang, W. S., Wang, D., Kaniowski, D., Kang, E. Y., Dizman, N., Chehrazi‐Raffle, A., Meza, L. A., Zengin, Z. B., Hall, J., et al. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1274781 · Cited by 19
Self-citationThe Dermis as a Portal for Dendritic Cell-Targeted Immunotherapy of Cutaneous Melanoma
Oosterhoff, D., Sluijter, B. J. R., Hangalapura, B. N., & de Gruijl, T. D. (2011) · Current topics in microbiology and immunology · doi:10.1007/82_2011_136 · Cited by 18
T Lymphocyte Subsets Profile and Toll-Like Receptors Responses in Patients with Herpes Zoster
Chen, W., Zhu, L., Shen, L.-L., Si, S., & Liu, J. (2023) · Journal of Pain Research · doi:10.2147/jpr.s405157 · Cited by 18
“After blocking STAT-3 signal pathway in peripheral blood leukocytes, macrophages and NK cells stimulated by TLR9 agonist CpG released a large amount of IFN-α and TNF-α, suggesting that TLR9 could rapidly activate macrophages and NK cells to release cytokines involved in the innate immune response.(49) In our work, the…”
BackgroundZhang, W., Pal, S. K., Liu, X., Yang, C., Allahabadi, S., Bhanji, S., Figlin, R. A., Yu, H., & Reckamp, K. L. (2013) · PLoS ONE · doi:10.1371/journal.pone.0065121 · Cited by 17
“Recent investigations demonstrate that inhibition of STAT3, which is constitutively activated in pre-metastatic niches, can decrease myeloid cell infiltration in future metastatic sites.[24,33] STAT3 also impairs antitumor immunity to facilitate carcinogen-induced lung tumor formation.”
BackgroundSelf-citationOligonucleotide delivery in cancer therapy
Rosa, G. D., Stefano, D. D., & Galeone, A. (2010) · Expert Opinion on Drug Delivery · doi:10.1517/17425247.2010.527942 · Cited by 17
“It has been shown that intratumoral injections of CpG ONs activate dendritic cells, leading to tumor regression in both mouse colon adenocarcinoma and melanoma [25,26], enhance the immune response and show a robust antitumor therapeutic activity, and elicit antitumor immune memory in a model of colon carcinoma [27].”
BackgroundThe Jak-STAT Signal Transduction Pathway in Melanoma
Nicholas, C., & Gregory, B. (2011) · InTech eBooks · doi:10.5772/18876 · Cited by 19
RNA Interference for the Treatment of Papillomavirus Disease
Singhania, R. (2012) · The Open Virology Journal · doi:10.2174/1874357901206010204 · Cited by 18
Local CpG-Stat3 siRNA treatment improves antitumor effects of immune checkpoint inhibitors
Zhang, C., Huang, R., Ren, L., Martincuks, A., Song, J., Kortylewski, M., Swiderski, P. M., Forman, S. J., & Yu, H. (2024) · Molecular Therapy — Nucleic Acids · doi:10.1016/j.omtn.2024.102357 · Cited by 16
Self-citationRemote Control of Intestinal Tumorigenesis by Innate Immunity
Sécher, T., Gaillot, O., Ryffel, B., & Chamaillard, M. (2010) · Cancer Research · doi:10.1158/0008-5472.can-09-3401 · Cited by 17
“Whereas STAT3 is activated by engagement of TLR-mediated signaling pathways and is critically involved in tumorigenesis and metastasis (21, 22), inactivation of STAT3 improved the tumoricidal potential of a TLR9-based immunotherapeutic approach (23).”
BackgroundGp130-dependent STAT3 activation in M–CSF–derived macrophages exaggerates tumor progression
Xu, Y., Xu, X., Zhang, Q., Lu, P., Xiang, C., Zhang, L., Lin, C., & Song, Q. (2023) · Genes & Diseases · doi:10.1016/j.gendis.2023.05.004 · Cited by 14
Synthetic immunostimulatory oligonucleotides in experimental and clinical practice
Bodera, P., Stankiewicz, W., & Kocik, J. (2012) · Pharmacological Reports · doi:10.1016/s1734-1140(12)70899-x · Cited by 14
“, secretion of Th1-promoting chemokines and cytokines [22].”
BackgroundDavar, D., Tarhini, A. A., & Kirkwood, J. M. (2011) · Journal of Skin Cancer · doi:10.1155/2011/274382 · Cited by 14
Khairuddin, N., Blake, S. J., Firdaus, F., Steptoe, R. J., Behlke, M. A., Hertzog, P. J., & McMillan, N. A. J. (2013) · Immunology and Cell Biology · doi:10.1038/icb.2013.75 · Cited by 13
STAT3: the “Achilles” heel for AML?
Rezvani, K., & Barrett, J. (2014) · Blood · doi:10.1182/blood-2013-11-537092 · Cited by 11
“They later showed that in the same way, ablating STAT3 in hematopoietic cells results in rapid activation of innate immunity by CpG (a TLR9 ligand), with enhanced production of interferon-g, tumor necrosis factor a, and interleukin-12 and activation of macrophages, neutrophils, and natural killer (NK) cells associated…”
BackgroundMicroglial TLR9: Plausible Novel Target for Therapeutic Regime Against Glioblastoma Multiforme
Tiwari, R., Singh, S., Gupta, C. L., & Bajpai, P. (2020) · Cellular and molecular neurobiology · doi:10.1007/s10571-020-00925-z · Cited by 8
Blaylock, R. L. (2019) · Surgical Neurology International · doi:10.25259/sni_361_2019 · Cited by 10
“[113,138,183,204] STAT3 can also be activated by other noninfectious stresses, including direct lipopolysaccharide stimulation through toll-like receptor 4 immune activation, UV light induction of skin cancer, chemical carcinogenesis, and chronic stress.[4,104,168] In the case of colitis-induced carcinoma, we see that…”
BackgroundInterface of Signal Transduction Inhibition and Immunotherapy in Melanoma
Shada, A. L., Molhoek, K. R., & Slingluff, C. L. (2010) · The Cancer Journal · doi:10.1097/ppo.0b013e3181eb3393 · Cited by 10
Clowers, M. J., & Moghaddam, S. J. (2022) · Cancers · doi:10.3390/cancers14071785 · Cited by 9
“Genetic ablation of STAT3 in macrophages results in increased pro-inflammatory cytokine production and increased antigen presentation to T cells [72].”
BackgroundImmune modulation strategies to reduce in-stent restenosis
Yu, M., Dai, C., Shi, J., & Fu, J. (2025) · Biomaterials Science · doi:10.1039/d5bm00687b · Cited by 10
Canha-Borges, A., Nunes, B., Quintas, S. T., Paredes, J., Meziani, L., Mondini, M., Oliveira, M. J., Deutsch, É., & Castro, F. (2025) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2025.103026 · Cited by 10
Breaking bad habits: Targeting MDSCs to alleviate immunosuppression in prostate cancer
Pal, S. K., & Kortylewski, M. (2015) · OncoImmunology · doi:10.1080/2162402x.2015.1078060 · Cited by 8
“mitochondrial DNA) from dying cells.(6,7)”
Self-citationDong, Y., Wang, L., Zhang, H., Li, M., Luo, Z. Y., Hu, Y., & Cai, C.-Y. (2025) · Advanced Science · doi:10.1002/advs.202512363 · Cited by 8
Self-citationMiller, C. L., Sagiv-Barfi, I., Neuhöfer, P., Czerwinski, D. K., Bertozzi, C. R., Cochran, J. R., & Levy, R. (2023) · The Journal of Immunology · doi:10.4049/jimmunol.2200950 · Cited by 7
Rodet, F., Capuz, A., Hara, T., van Meel, R., Duhamel, M., Rose, M., Raffo‐Romero, A., Fournier, I., & Salzet, M. (2018) · Journal of Biotechnology · doi:10.1016/j.jbiotec.2018.07.002 · Cited by 6
Lu, J., Lin, L., Sun, Y., Liu, D., & Gong, Z. (2022) · Biomedicines · doi:10.3390/biomedicines10010095 · Cited by 5
Multifunctional aptamer grafted targeted nano‐drugs execute molecular cross‐talks with cancer cells
Manna, S., Mahata, R., Dey, S. K., Chaudhuri, A. D., & Choudhury, S. M. (2024) · Applied Research · doi:10.1002/appl.202300115 · Cited by 4
Decoy-Based, Targeted Inhibition of STAT3: A New Step forward for B Cell Lymphoma Immunotherapy
Soldevilla, M. M., & Pastor, F. (2018) · Molecular Therapy · doi:10.1016/j.ymthe.2018.02.006 · Cited by 4
“STAT3 is frequently activated in solid tumors and hematological malignancies such as myeloma and lymphoma.(3,4) Different approaches have been tested to inhibit STAT3 over the past few years, yet no inhibitory drug or small molecule has been approved by the Federal Drug Administration (FDA).”
Background
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
