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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TLRs such as TLR2, TLR4, TLR7 and TLR9 activate STAT3.
“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]
The Results section (‘Direct and rapid induction of Stat3 activity in DCs’; page unavailable) reports STAT3 activation by the TLR4 agonist LPS and by CpG, which the paper identifies as acting through TLR9. The passages do not establish that TLR2 or TLR7 activate STAT3, so this source supports only two of the four receptors listed. (LLM, conf=0.88)
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Cites
Akira, S., & Takeda, K. (2004) · Nature reviews. Immunology · doi:10.1038/nri1391 · Cited by 8,312 · see citing works
Toll Pathway-Dependent Blockade of CD4+CD25+ T Cell-Mediated Suppression by Dendritic Cells
Pasare, C., & Medzhitov, R. (2003) · Science · doi:10.1126/science.1078231 · Cited by 2,327 · cited 1× · see citing works
“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).”
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× · see citing works
“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-citationGabrilovich, 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 · see citing works
Inducible Gene Targeting in Mice
Kühn, R., Schwenk, F., Aguet, M., & Rajewsky, K. (1995) · Science · doi:10.1126/science.7660125 · Cited by 1,915 · cited 1× · see citing works
“In the Cre-loxP system, in addition to hematopoietic cells, some organs also undergo partial Stat3 truncation upon poly(I/C) treatment (21).”
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 1,809 · cited 6× · see citing works
“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-citationTakeda, 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 · see citing works
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 1,214 · cited 1× · see citing works
“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).”
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 1,159 · cited 5× · see citing works
“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-citationInhibiting 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× · see citing works
“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× · see citing works
“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).”
Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome
Minegishi, Y., Saito, M., Tsuchiya, S., Tsuge, I., Takada, H., Hara, T., Kawamura, N., Ariga, T., Pasic, S., Stojković, O., et al. (2007) · Nature · doi:10.1038/nature06096 · Cited by 987 · see citing works
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× · see citing works
“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× · see citing works
“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 630 · see citing works
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 581 · cited 2× · see citing works
“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× · see citing works
“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× · see citing works
“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× · see citing works
“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 381 · cited 1× · see citing works
“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 · see citing works
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× · see citing works
“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× · see citing works
“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 · see citing works
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× · see citing works
“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 218 · cited 1× · see citing works
“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 · see citing works
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 159 · cited 1× · see citing works
“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).”
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 151 · cited 8× · see citing works
“For treatment using Stat3 inhibitor CPA7 (12, 16), B16 and C4 tumors were”
InfluentialPallandre, 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 151 · cited 1× · see citing works
“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).”
Appay, 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 150 · cited 1× · see citing works
“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× · see citing works
“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 · see citing works
Flagged first, then by citations
1 of the 34 references couldn’t be matched to a known paper.
Research works printed but not linked: 1
- [29]Kujawski M Kortylewski M Lee H Herrmann A Kay H Yu H Stat3 mediates myeloid-cell-dependent tumor angiogenesis J Clin Invest 2008 118 3367 77 18776941 PMC2528912
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 · see citing works
“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 · see citing works
Self-citationIL-6 in inflammation, autoimmunity and cancer
Hirano, T. (2021) · International Immunology · doi:10.1093/intimm/dxaa078 · Cited by 1,453 · see citing works
“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 692 · see citing works
Aptamer-based targeted therapy
Zhu, G., & Chen, X. (2018) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2018.08.005 · Cited by 522 · see citing works
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 511 · see citing works
“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 378 · see citing works
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 340 · see citing works
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 266 · see citing works
“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 256 · see citing works
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 252 · see citing works
“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.-F. (2015) · Scientific Reports · doi:10.1038/srep17663 · Cited by 235 · see citing works
Rébé, C., Végran, F., Berger, H., & Ghiringhelli, F. (2013) · JAK-STAT · doi:10.4161/jkst.23010 · Cited by 216 · see citing works
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 194 · see citing works
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 188 · see citing works
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 · see citing works
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 189 · see citing works
“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 190 · see citing works
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 178 · see citing works
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 · see citing works
STAT3: An Emerging Therapeutic Target for Hepatocellular Carcinoma
Lee, C., & Cheung, S. (2019) · Cancers · doi:10.3390/cancers11111646 · Cited by 142 · see citing works
“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 134 · see citing works
“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 132 · see citing works
“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 · see citing works
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 · see citing works
“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 123 · see citing works
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 · see citing works
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 · see citing works
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 108 · see citing works
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 · see citing works
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 · see citing works
Self-citationThe revival of CpG oligonucleotide-based cancer immunotherapies
Adamus, T., & Kortylewski, M. (2018) · Współczesna Onkologia · doi:10.5114/wo.2018.73887 · Cited by 98 · see citing works
“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 · see citing works
“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 88 · see citing works
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 81 · see citing works
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 · see citing works
“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 · see citing works
“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 · see citing works
“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 76 · see citing works
“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 73 · see citing works
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 · see citing works
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 · see citing works
Stephen, Z. R., & Zhang, M. (2020) · Advanced Healthcare Materials · doi:10.1002/adhm.202001415 · Cited by 70 · see citing works
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 69 · see citing works
Self-citationTh1 cytokine-based immunotherapy for cancer
Xu, H. (2014) · Hepatobiliary & pancreatic diseases international · doi:10.1016/s1499-3872(14)60305-2 · Cited by 66 · see citing works
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 64 · see citing works
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 · see citing works
“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 · see citing works
“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 · see citing works
Hashimoto, S., Hashimoto, A., Muromoto, R., Kitai, Y., Oritani, K., & Matsuda, T. (2022) · Cells · doi:10.3390/cells11162618 · Cited by 50 · see citing works
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 · see citing works
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 48 · see citing works
“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 · see citing works
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 · see citing works
Self-citationGonzález-Ávila, G., Sommer, B., Flores‐Soto, E., & Aquino‐Gálvez, A. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms242316887 · Cited by 42 · see citing works
“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 42 · see citing works
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 40 · see citing works
“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 · see citing works
“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 · see citing works
“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 · see citing works
“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 · see citing works
“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 36 · see citing works
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 35 · see citing works
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 · see citing works
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 35 · see citing works
“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 · see citing works
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 · see citing works
“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 · see citing works
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 · see citing works
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 · see citing works
Mojiri-Forushani, H., Khajehali, E., Adelipour, M., & Mohammadi, A. (2022) · Molecular Biology Reports · doi:10.1007/s11033-022-08219-x · Cited by 24 · see citing works
“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 19 · see citing works
“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 · see citing works
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 · see citing works
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 · see citing works
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 17 · see citing works
“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 · see citing works
“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 · see citing works
“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 17 · see citing works
RNA Interference for the Treatment of Papillomavirus Disease
Singhania, R. (2012) · The Open Virology Journal · doi:10.2174/1874357901206010204 · Cited by 16 · see citing works
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 15 · see citing works
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 15 · see citing works
“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 · see citing works
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 · see citing works
“, 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 · see citing works
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 · see citing works
STAT3: the “Achilles” heel for AML?
Rezvani, K., & Barrett, J. (2014) · Blood · doi:10.1182/blood-2013-11-537092 · Cited by 11 · see citing works
“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 · see citing works
Blaylock, R. L. (2019) · Surgical Neurology International · doi:10.25259/sni_361_2019 · Cited by 10 · see citing works
“[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 · see citing works
Clowers, M. J., & Moghaddam, S. J. (2022) · Cancers · doi:10.3390/cancers14071785 · Cited by 9 · see citing works
“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 · see citing works
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 8 · see citing works
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 · see citing works
“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 7 · see citing works
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 · see citing works
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 · see citing works
Lu, J., Lin, L., Sun, Y., Liu, D., & Gong, Z. (2022) · Biomedicines · doi:10.3390/biomedicines10010095 · Cited by 5 · see citing works
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 · see citing works
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 · see citing works
“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
- 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
- Health Sciences › Medicine › Oncology › 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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