TLR9 Agonists Oppositely Modulate DNA Repair Genes in Tumor versus Immune Cells and Enhance Chemotherapy Effects
ABSTRACT 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.
Full-textDOI: · Available from: Michele Sommariva, May 15, 2014
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ABSTRACT: Toll-like receptors (TLRs) are germ line encoded innate immune sensors that recognize conserved microbial structures and host alarmins, and signal expression of major histocompatibility complex proteins, costimulatory molecules, and inflammatory mediators by macrophages, neutrophils, dendritic cells, and other cell types. These protein receptors are characterized by their ability to respond to invading pathogens promptly by recognizing particular TLR ligands, including flagellin and lipopolysaccharide of bacteria, nucleic acids derived from viruses, and zymosan of fungi. There are 2 major TLR pathways; one is mediated by myeloid differentiation factor 88 (MYD88) adaptor proteins, and the other is independent of MYD88. The MYD88-dependent pathway involves early-phase activation of nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (NF-κB1) and all the TLRs, except TLR3, have been shown to activate this pathway. TLR3 and TLR4 act via MYD88-independent pathways with delayed activation of NF-κB signaling. TLRs play a vital role in activating immune responses. TLRs have been shown to mediate inflammatory responses and maintain epithelial barrier homeostasis, and are highly likely to be involved in the activation of a number of pathways following cancer therapy. Colorectal cancer (CRC) is one of the most common cancers, and accounts for almost half a million deaths annually worldwide. Inflammation is considered a risk factor for many common malignancies including cancers of the colorectum. The key molecules involved in inflammation-driven carcinogenesis include TLRs. As sensors of cell death and tissue remodeling, TLRs may have a universal role in cancer; stimulation of TLRs to activate the innate immune system has been a legitimate therapeutic strategy for some years. TLRs 3/4/7/8/9 are all validated targets for cancer therapy, and a number of companies are developing agonists and vaccine adjuvants. On the other hand, antagonists may favor inhibition of signaling responsible for autoimmune responses. In this paper, we review TLR signaling in CRC from carcinogenesis to cancer therapy.World Journal of Gastroenterology 12/2014; 20(47):17699-17708. DOI:10.3748/wjg.v20.i47.17699 · 2.43 Impact Factor
Frontiers in Immunology 07/2014; 5(343):1-5. DOI:10.3389/fimmu.2014.00343
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ABSTRACT: UVB-induced DNA damage plays a critical role in development of photoimmunosuppression. The purpose of this study was to determine whether repair of UVB-induced DNA damage is regulated by Toll-like receptor-4 (TLR4). When TLR4 gene knockout (TLR4(-/-)) and TLR4 competent (TLR4(+/+)) mice were subjected to 90 mJ/cm(2) UVB radiation locally, DNA damage in the form of CPD, were repaired more efficiently in the skin and bone marrow dendritic cells (BMDC) of TLR4(-/-) mice in comparison to TLR4(+/+) mice. Expression of DNA repair gene XPA (Xeroderma pigmentosum complementation group A) was significantly lower in skin and BMDC of TLR4(+/+) mice than TLR4(-/-) mice after UVB exposure. When cytokine levels were compared in these strains after UVB exposure, BMDC from UV-irradiated TLR4(-/-) mice produced significantly more interleukin (IL)-12 and IL-23 cytokines (P<0.05) than BMDC from TLR4(+/+) mice. Addition of anti-IL-12 and anti-IL-23 antibodies to BMDC of TLR4(-/-) mice (before UVB exposure) inhibited repair of CPD, with a concomitant decrease in XPA expression. Addition of TLR4 agonist to TLR4(+/+) BMDC cultures decreased XPA expression and inhibited CPD repair. Thus, strategies to inhibit TLR4 may allow for immunopreventive and immunotherapeutic approaches for managing UVB-induced cutaneous DNA damage and skin cancer.Journal of Investigative Dermatology accepted article preview online, 10 December 2013. doi:10.1038/jid.2013.530.Journal of Investigative Dermatology 12/2013; 134(6). DOI:10.1038/jid.2013.530 · 6.37 Impact Factor