Treatment Failure of a TLR-7 Agonist Occurs Due to Self-Regulation of Acute Inflammation and Can Be Overcome by IL-10 Blockade

Lu, Hailing; Wagner, Wolfgang; Gad, Ekram; Yang, Yi; Duan, Hangjun; Amon, Lynn M.; Denend, Nathaniel Van; Larson, Emily R.; Chang, Amy; Tufvesson, Helena; Disis, Mary L.

doi:10.4049/jimmunol.0902997

Cited by 71 publications

(73 citation statements)

References 44 publications

(44 reference statements)

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“…9 However, we have not detected IL-10 by ELISA in supernatants of our B16-OVA cells, even after in vitro stimulation with IL-10-inducing TLR ligands (data not shown), despite TLR expression in these cells. 37 CD4 C T cells have been reported as IL-10 producers after Imiquimod administration 29 in a breast tumor model, suggesting that these cells may also produce IL-10 in our model. However, the early detection of IL-10 after Imiquimod administration (1-2 d) suggests that innate immunity may play an important role in IL-10 production.…”

Section: Discussionmentioning

confidence: 69%

Vaccine-induced but not tumor-derived Interleukin-10 dictates the efficacy of Interleukin-10 blockade in therapeutic vaccination

et al. 2015

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Section: Discussionmentioning

confidence: 69%

Vaccine-induced but not tumor-derived Interleukin-10 dictates the efficacy of Interleukin-10 blockade in therapeutic vaccination

et al. 2015

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“…Despite numerous previous microarray analyses of immune cells after in vitro or in vivo stimulation with CpG-ODN (26,33,35,43,47), to our knowledge, an upregulation of DNA repair genes after CpG-ODN treatment has not been reported. This might reflect a primary focus in previous studies on signaling pathways that induce expression of immune and proinflammatory genes (48), in light of the function of TLRs as innate immunity sensors of microbial products.…”

Section: Discussionmentioning

confidence: 82%

TLR9 Agonists Oppositely Modulate DNA Repair Genes in Tumor versus Immune Cells and Enhance Chemotherapy Effects

et al. 2011

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Synthetic oligodeoxynucleotides expressing CpG motifs (CpG-ODN) are a Toll-like receptor 9 (TLR9) agonist that can enhance the antitumor activity of DNA-damaging chemotherapy and radiation therapy in preclinical mouse models. We hypothesized that the success of these combinations is related to the ability of CpG-ODN to modulate genes involved in DNA repair. We conducted an in silico analysis of genes implicated in DNA repair in data sets obtained from murine colon carcinoma cells in mice injected intratumorally with CpG-ODN and from splenocytes in mice treated intraperitoneally with CpG-ODN. CpG-ODN treatment caused downregulation of DNA repair genes in tumors. Microarray analyses of human IGROV-1 ovarian carcinoma xenografts in mice treated intraperitoneally with CpG-ODN confirmed in silico findings. When combined with the DNA-damaging drug cisplatin, CpG-ODN significantly increased the life span of mice compared with individual treatments. In contrast, CpG-ODN led to an upregulation of genes involved in DNA repair in immune cells. Cisplatin-treated patients with ovarian carcinoma as well as anthracycline-treated patients with breast cancer who are classified as "CpG-like" for the level of expression of CpG-ODN modulated DNA repair genes have a better outcome than patients classified as "CpG-untreated-like," indicating the relevance of these genes in the tumor cell response to DNA-damaging drugs. Taken together, the findings provide evidence that the tumor microenvironment can sensitize cancer cells to DNA-damaging chemotherapy, thereby expanding the benefits of CpG-ODN therapy beyond induction of a strong immune response. Cancer Res; 71(20); 6382-90. Ó2011 AACR.

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“…In neoplastic processes without an evident primary inflammatory component, TLR ligation may break self-antigen tolerance, promoting antitumor immune responses (46). For example, in neu transgenic mice, an attractive model mimicking human Her-2/neu + breast cancer, TLR7 ligation elicits significant tumor regression by augmenting antitumor immunity (47). However, in neoplastic conditions that arise from inflammation and are driven by continued inflammation, such as pancreatic cancer associated with longstanding pancreatitis, selective TLR ligation may be protumorigenic.…”

Section: Figurementioning

confidence: 99%

Toll-like receptor 7 regulates pancreatic carcinogenesis in mice and humans

et al. 2012

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Pancreatic ductal adenocarcinoma is an aggressive cancer that interacts with stromal cells to produce a highly inflammatory tumor microenvironment that promotes tumor growth and invasiveness. The precise interplay between tumor and stroma remains poorly understood. TLRs mediate interactions between environmental stimuli and innate immunity and trigger proinflammatory signaling cascades. Our finding that TLR7 expression is upregulated in both epithelial and stromal compartments in human and murine pancreatic cancer led us to postulate that carcinogenesis is dependent on TLR7 signaling. In a mouse model of pancreatic cancer, TLR7 ligation vigorously accelerated tumor progression and induced loss of expression of PTEN, p16, and cyclin D1 and upregulation of p21, p27, p53, c-Myc, SHPTP1, TGF-β, PPARγ, and cyclin B1. Furthermore, TLR7 ligation induced STAT3 activation and interfaced with Notch as well as canonical NF-κB and MAP kinase pathways, but downregulated expression of Notch target genes. Moreover, blockade of TLR7 protected against carcinogenesis. Since pancreatic tumorigenesis requires stromal expansion, we proposed that TLR7 ligation modulates pancreatic cancer by driving stromal inflammation. Accordingly, we found that mice lacking TLR7 exclusively within their inflammatory cells were protected from neoplasia. These data suggest that targeting TLR7 holds promise for treatment of human pancreatic cancer.

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Treatment Failure of a TLR-7 Agonist Occurs Due to Self-Regulation of Acute Inflammation and Can Be Overcome by IL-10 Blockade

Abstract: Material

Cited by 71 publications

References 44 publications

Vaccine-induced but not tumor-derived Interleukin-10 dictates the efficacy of Interleukin-10 blockade in therapeutic vaccination

Vaccine-induced but not tumor-derived Interleukin-10 dictates the efficacy of Interleukin-10 blockade in therapeutic vaccination

TLR9 Agonists Oppositely Modulate DNA Repair Genes in Tumor versus Immune Cells and Enhance Chemotherapy Effects

Toll-like receptor 7 regulates pancreatic carcinogenesis in mice and humans

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