Molecular basis for the immunostimulatory activity of guanine nucleoside analogs: Activation of Toll-like receptor 7

Lee, Jongdae; Chuang, Tsung‐Hsien; Redecke, Vanessa; She, Liping; Pitha, Paula M.; Carson, Dennis A.; Raz, Eyal; Cottam, Howard B.

doi:10.1073/pnas.0631696100

Cited by 531 publications

(435 citation statements)

References 35 publications

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“…28 We cannot exclude the possibility of immune system activation by the primary and secondary structures of mRNA via TLR3, TLR7 and TLR8 Toll-like receptors of DCs. [40][41][42][43][44][45][46] Similar contribution from MART1 mRNA lipopolyplexes could be explored using gene-deficient mice. In our system, the effect of MART1 mRNA immunization was much higher than of MART1 DNA immunization because DNA transfection of APC requires the plasmid import in the nucleus.…”

Section: Discussionmentioning

confidence: 99%

mRNA-based cancer vaccine: prevention of B16 melanoma progression and metastasis by systemic injection of MART1 mRNA histidylated lipopolyplexes

et al. 2007

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Immunization with mRNA encoding tumor antigen is an emerging vaccine strategy for cancer. In this paper, we demonstrate that mice receiving systemic injections of MART1 mRNA histidylated lipopolyplexes were specifically and significantly protected against B16F10 melanoma tumor progression. The originality of this work concerns the use of a new tumor antigen mRNA formulation as vaccine, which allows an efficient protection against the growth of a highly aggressive tumor model after its delivery by intravenous route. Synthetic melanoma-associated antigen MART1 mRNA was formulated with a polyethylene glycol (PEG)ylated derivative of histidylated polylysine and L-histidine-(N,N-di-n-hexadecylamine)ethylamide liposomes (termed histidylated lipopolyplexes). Lipopolyplexes comprised mRNA/polymer complexes encapsulated by liposomes. The tumor protective effect was induced with MART1 mRNA carrying a poly(A) tail length of 100 adenosines at an optimal dose of 12.5 mg per mouse. MART1 mRNA lipopolyplexes elicited a cellular immune response characterized by the production of interferon-g and the induction of cytotoxic T lymphocytes. Finally, the anti-B16 response was enhanced using a formulation containing both MART1 mRNA and MART1-LAMP1 mRNA encoding the antigen targeted to the major histocompatibility complex class II compartments by the lysosomal sorting signal of LAMP1 protein. Our results provide a basis for the development of mRNA histidylated lipopolyplexes for cancer vaccine.

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Section: Discussionmentioning

confidence: 99%

mRNA-based cancer vaccine: prevention of B16 melanoma progression and metastasis by systemic injection of MART1 mRNA histidylated lipopolyplexes

et al. 2007

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“…Synthetic small molecules such as imidazoquinolines and certain nucleoside analogues activate TLR7 and/or TLR8 (3,24). Imiquimod, a TLR7 agonist, has been approved as a topical agent for the treatment of superficial basal cell carcinoma and actinic keratosis (25,26).…”

Section: Discussionmentioning

confidence: 99%

Antitumor Activity and Immune Response Induction of a Dual Agonist of Toll-Like Receptors 7 and 8

Wang

Precopio

Lan

et al. 2010

Molecular Cancer Therapeutics

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Viral and synthetic single-stranded RNAs are the ligands for Toll-like receptors 7 and 8 (TLR7 and TLR8). We have reported a novel class of synthetic oligoribonucleotides, referred to as stabilized immunemodulatory RNA compounds, which act as agonists of TLR7, TLR8, or both TLR7 and TLR8 depending on the sequence composition and the presence of specific chemical modifications. In the present study, we evaluated the antitumor activity of a dual TLR7/8 agonist in tumor-bearing mice with peritoneal disseminated CT26.CL25 colon and 3LL-C75 lung carcinomas. Peritoneal administration of dual TLR7/8 agonist in mice bearing CT26.CL25 colon carcinomas had potent dose-dependent antitumor activity, which was associated with a marked decrease in CD4 + CD25 + Foxp3 + T regulatory cells and a significant increase in tumor antigen-specific IFN-γ-secreting effector cell responses in splenocytes and local tumor-infiltrating cells. In 3LL-C75 lung carcinoma, dual TLR7/8 agonist induced strong immune responses and antitumor effects in C57BL/6 and TLR9 −/− mice, but not in TLR7 −/− and MyD88 −/− mice, indicating that the agonist induces immune responses via TLR7 and through the MyD88-dependent signaling pathway. TLR8 is not functional in mice. Additionally, s.c. administration of TLR7/8 agonist effectively prevented lung metastasis of tumors in the CT26.CL25 pulmonary metastasis model. These studies show that the dual TLR7/8 agonist induced Th1-type immune responses and potent antitumor activity in mice via TLR7 and through the MyD88-dependent pathway. Mol Cancer Ther; 9(6); 1788-97. ©2010 AACR.

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“…To determine if the lack of detectable expression of TLR7 mRNA resulted in unresponsiveness to TLR7 ligands, CD172a high iL-DC were stimulated in vitro with Loxoribine, a TLR7-specific ligand [22], and secreted IL-12p40 was measured. Very little if any IL-12p40 was secreted after stimulation with Loxoribine, while coincubation with R-848 resulted in significant secretion of the cytokine (Fig.…”

Section: Differential Expression Of Tlr7 and Tlr8 By Il-dc Subsetsmentioning

confidence: 99%

A distinct subset of intestinal dendritic cells responds selectively to oral TLR7/8 stimulation

Yrlid¹,

Cerovic

Milling³

et al. 2006

Eur J Immunol

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The intestinal innate immune system continually interacts with commensal bacteria, thus oral vaccines should induce extra/alternative activation of DC, potentially through TLR. To examine this we collected intestinal lymph DC (iL-DC) under steady-state conditions and after feeding resiquimod (R-848), a synthetic TLR7/8 ligand, which we showed induces complete emptying of gut DC into lymph. iL-DC are heterogeneous with subset-specific functions. In this study we determined the kinetics of iL-DC subset release, activation and cytokine secretion induced by R-848. We show that L-DC comprise three distinct subsets (CD172a high , CD172a int and CD172a low ) present with similar frequencies in intestinal but not hepatic lymph. No iL-DC express TLR7 mRNA, and only CD172a + iL-DC express TLR8. However, after oral R-848 administration, output of all three subsets increases dramatically. CD172a high DC release precedes that of CD172a low DC, and the increased frequency of CD25 high iL-DC is restricted to the two CD172a + subsets. After feeding R-848 only CD172a high iL-DC secrete IL-6 and IL-12p40. However, CD172a int and CD172a high DC secrete similar but markedly lower amounts when stimulated in vitro. These results highlight the importance of in vivo approaches to assess adjuvant effects on DC and give novel insights into the subset-specific effects of an oral TLR ligand on intestinal DC.

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Molecular basis for the immunostimulatory activity of guanine nucleoside analogs: Activation of Toll-like receptor 7

Cited by 531 publications

References 35 publications

mRNA-based cancer vaccine: prevention of B16 melanoma progression and metastasis by systemic injection of MART1 mRNA histidylated lipopolyplexes

mRNA-based cancer vaccine: prevention of B16 melanoma progression and metastasis by systemic injection of MART1 mRNA histidylated lipopolyplexes

Antitumor Activity and Immune Response Induction of a Dual Agonist of Toll-Like Receptors 7 and 8

A distinct subset of intestinal dendritic cells responds selectively to oral TLR7/8 stimulation

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