TLR9 Is Critical for Glioma Stem Cell Maintenance and Targeting

Herrmann, Andreas; Cherryholmes, Gregory; Schroeder, Anne; Phallen, Jillian; Alizadeh, Darya; Hong, Xin; Wang, Tianyi; Lee, Heehyoung; Lahtz, Christoph; Swiderski, Piotr; Armstrong, Brian; Kowolik, Claudia; Gallia, Gary L.; Lim, Michael; Brown, Christine E.; Badie, Behnam; Forman, Stephen J.; Kortylewski, Marcin; Jove, Richard; Yu, Hua

doi:10.1158/0008-5472.can-14-1151

Cited by 63 publications

(68 citation statements)

References 49 publications

(78 reference statements)

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“…Importantly, the percentage of CD5 + B cells was significantly expanded in tumors (Figure 1A). STAT3 is a transcription factor known to upregulate expression of several of its own upstream activators (Herrmann et al, 2014; Kortylewski et al, 2009; Lee et al, 2010; Xin et al, 2013; Yu et al, 2009). We therefore explored the possibility that STAT3 upregulates CD5 expression, thereby forming a feed-forward loop in B cells to promote tumor progression.…”

Section: Resultsmentioning

confidence: 99%

“…Activation of STAT3 in tumor cells and in the tumor microenvironment is contributed by many factors, albeit a critical role of IL-6 (Kujawski et al, 2008; Wang et al, 2009). In addition to multiple cytokines and growth factors, chemokines and other ligands of GPCRs including sphingosine-1-phosphate (S1P), have been shown to be critical for persistent activation of STAT3 in tumor, including many types of immune cells in the tumor microenvironment (Deng et al, 2012; Herrmann et al, 2014; Lee et al, 2010; Lee et al, 2009). A common feature of STAT3 activation is that STAT3 regulates expression of their receptors, which in turn activate STAT3, even in the absence of abundant amounts of their ligands.…”

Section: Discussionmentioning

confidence: 99%

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CD5 Binds to Interleukin-6 and Induces a Feed-Forward Loop with the Transcription Factor STAT3 in B Cells to Promote Cancer

et al. 2016

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SUMMARY The participation of a specific subset of B cells and how they are regulated in cancer is unclear. Here, we demonstrate that the proportion of CD5+ relative to interleukin-6 receptor α (IL-6Rα) expressing B cells was greatly increased in tumors. CD5+ B cells responded to IL-6 in the absence of IL-6Rα. IL-6 directly bound to CD5, leading to activation of the transcription factor STAT3 via gp130 and its downstream kinase JAK2. STAT3 upregulated CD5 expression, thereby forming a feed-forward loop in the B cells. In mouse tumor models, CD5+ but not CD5−B cells promoted tumor growth. CD5+ B cells also showed activation of STAT3 in multiple types of human tumor tissues. Thus, our findings demonstrate a critical role of CD5+ B cells in promoting cancer.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

CD5 Binds to Interleukin-6 and Induces a Feed-Forward Loop with the Transcription Factor STAT3 in B Cells to Promote Cancer

et al. 2016

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“…Moreover, high contents of stromal inflammation, CAFs and MICs overexpressing TLR9 and numerous cytotoxic CD8 lymphocytes were also associated with a better prognosis [43]. Cancer-associated chronic inflammation initiated by epithelial cancer cells and stromal/immune cells overexpressing TLR9, is amplified and sustained by a chemokine inducer composed of activated NF-kB and STAT3 [44,45] which may promote cancer progression and therapeutic resistance [46]. Furthermore, several studies identified TLRs, such as TLR9, as crucial activators of the JAK-STAT3 pathway.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, several studies identified TLRs, such as TLR9, as crucial activators of the JAK-STAT3 pathway. Recent data showed that TLR9 is highly expressed in glioblastoma stem-like cells (GSCs) [46] and that activated STAT3 binds to the TLR9 promoter and contributes to TLR9 expression in GSCs [47], providing a potential mechanism by which infection or inflammation enhances carcinogenesis. In our series of 80 TNCs, we observed that in TNCs with TLR9 overexpression, nuclear phosphoSTAT3 (Tyr705) was identified in 81 % of cancer cells as compared to 31 % of cancer cells in TNCs with normal or low TLR9 level of expression.…”

Section: Discussionmentioning

confidence: 99%

Biopathological Significance of TLR9 Expression in Cancer Cells and Tumor Microenvironment Across Invasive Breast Carcinomas Subtypes

Meseure

Vacher

Alsibai

et al. 2016

Cancer Microenvironment

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Toll-like receptors (TLRs) are pattern recognition receptors mainly expressed by cells of the immune system but also by epithelial tumor cells. Little is known about expression patterns of TLR genes in breast tumors, and their clinical significance is unclear. The aim of our study was to investigate expression of TLRs pathway components in pre-invasive breast lesions and invasive breast carcinomas (IBCs). We used RT-PCR assays to quantify mRNA levels of the 10 TLR genes and genes involved in TLR pathways in 350 breast tumors from patients with known clinical/pathological status and long-term outcome. Sets of 158 breast samples were also analyzed by immunochemistry including; 40 early noninvasive breast lesions, 38 IBCs and 80 triple negative carcinomas subtype (TNCs). We identified TLR9 as the major TLR gene family member upregulated in breast tumors and more particularly in TNCs. Immunohistochemical studies demonstrated that TLR9 protein was expressed in tumor epithelial and stromal cells of the TLR9 mRNA-overexpressing tumors. TLR9 overexpression appears very early during breast carcinogenesis. High TLR9 levels were associated with favorable outcome in the TNC sub-group. TLR9 overexpression was associated with alterations of down-stream components of the TLR9 signaling pathway, epithelio-mesenchymal transition (EMT) induction and EGFR pathway deregulation. TNCs with TLR9 overexpression were significantly correlated with development of a fibrous and inflammatory microenvironment with variable status of nuclear phosphoSTAT3. Our results suggest that TLR9 could play a role in TNC carcinogenesis and could be useful as predictive biomarker and therapeutic target.Keywords Toll-like receptor 9 . Breast cancer subtypes .

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“…[12, 35] TLR9 is also commonly elevated in cancer cells in many hematologic malignancies, including acute myeloid leukemia (AML), multiple myeloma and B cell lymphoma as well as in certain solid tumors, such as prostate cancers or malignant glioma. [23, 36–38] The efficacy of CpG-conjugates is determined not only by TLR9, as TLR9 partners with SRs on the cell surface for conjugate uptake. Noteworthy, SRs expression has been reported in hematologic malignancies and also in various solid tumors, e.g.…”

Section: It Takes Two To Deliver: Tlr9 and Scavenger Receptorsmentioning

confidence: 99%

Myeloid cells as a target for oligonucleotide therapeutics: turning obstacles into opportunities

Kortylewski

Moreira

2017

Cancer Immunol Immunother

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Immunotherapies emerged as an alternative for cancer treatment, yet their clinical efficacies are still limited, especially in case of solid tumors. Myeloid immune cells, such as macrophages and myeloid-derived suppressor cells (MDSCs), are often hijacked by tumors and become pivotal inhibitors of antitumor immunity. Immunosuppressive functions of tumor-associated myeloid cells result from the activity of Signal Transducer and Activator of Transcription 3 (STAT3), a transcription factor with well-defined tumorigenic and tolerogenic roles in human cancers. To overcome challenges in the development of pharmacological STAT3 inhibitors, we recently developed oligonucleotide-based strategies for cell-selective, in vivo STAT3 targeting. Conjugation of a STAT3siRNA or decoy STAT3 inhibitors to synthetic Toll-like Receptor 9 (TLR9) agonists, CpG oligonucleotides, allowed for selective delivery into TLR9-positive cells. Cellular targets for CpG-STAT3 inhibitors include non-malignant, tumor-associated myeloid cells, such as polymorphonuclear MDSCs, as well as cancer cells in acute myeloid leukemia, B cell lymphoma and in certain solid tumors. The chemically modified CpG-STAT3 inhibitors resist blood nucleases and thus can be administered intravenously. Their potency relies on the intracellular gain-of-function effect: release of the central immune checkpoint regulator (STAT3) to unleash proinflammatory signaling (CpG/TLR9) in the same antigen-presenting cell. At the cellular level, CpG-STAT3 inhibitors exert two-pronged effect by rescuing T cells from the immune checkpoint control while decreasing survival of cancer cells. In this article, we review the preclinical data on CpG-STAT3 inhibitors and discuss perspectives of using TLR9-targeted delivery of oligonucleotide therapeutics for the generation of novel, more effective and safer cancer immunotherapies.

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TLR9 Is Critical for Glioma Stem Cell Maintenance and Targeting

Cited by 63 publications

References 49 publications

CD5 Binds to Interleukin-6 and Induces a Feed-Forward Loop with the Transcription Factor STAT3 in B Cells to Promote Cancer

CD5 Binds to Interleukin-6 and Induces a Feed-Forward Loop with the Transcription Factor STAT3 in B Cells to Promote Cancer

Biopathological Significance of TLR9 Expression in Cancer Cells and Tumor Microenvironment Across Invasive Breast Carcinomas Subtypes

Myeloid cells as a target for oligonucleotide therapeutics: turning obstacles into opportunities

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