TLR7 Gene Editing

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TLR7 Gene Editing    

Toll-like receptors (TLRs) represent the major pathway by which microorganisms interact with host cells. They are a family of highly conserved pattern-recognition receptors that recognize distinct pathogen-associated molecular patterns that are conserved in specific classes of microorganisms. The human TLR family consists of at least ten members that can be divided into surface-expressed TLRs (TLR1, TLR2, TLR4, TLR5, TLR6 and TLR10) and endosomal TLRs (TLR3, TLR7, TLR8 and TLR9). Toll-like receptor 7 (TLR7) is expressed on endosomes in immune cells including macrophages, plasmacytoid and conventional dendritic cells (pDC and cDC), NK cells and B lymphocytes. It is an innate immune sensor for single-strand RNA (ssRNA). Recent structural analysis showed that TLR7 has an additional binding site for nucleosides such as guanosine, and is activated when both guanosine and ssRNA bind. The nucleoside binding site also accommodates imidazoquinoline derivatives such as R848, which activate TLR7 without ssRNA.

TLR7 agonist in cancer therapy

The potency of TLR ligands for immune activation has led the way to develop them as therapeutic agents against cancer and infectious diseases. TLR7 has a restricted expression pattern and functional expression is mostly seen in plasmacytoid dendritic cells (pDCs), myeloid dendritic cells (mDCs), and B cells. Dendritic cells, especially pDCs are key to TLR7-targeted therapy. In pDCs, TLR7 engagement induces NF-κB and IRF7 activation in a MyD88-dependent fashion. Downstream signaling matures pDCs and induces proinflammatory cytokines and IFN-α, which is the main mediator of TLR7 agonist effects. However, pDCs have a potential dual role. They not only translate the detection of TLR7 ligands by cytokine induction to other effector cells, but can mature themselves to effector cells with tumor killing capacities of their own. Effector T cells are activated and matured under the influence of TLR7 agonists and are key to their therapeutic efficacy. NK cells are also potent effectors for TLR7 agonist activity, but their effect may be restricted to tumors that are inherently sensitive to NK-cell-mediated killing.

Overview of the main terminal effector cells of TLR7 agonists.Figure 1. Overview of the main terminal effector cells of TLR7 agonists. (Kobold S, et al. 2014)

The use of TLR7 agonists such as loxoribine, imiquimod, R848, CL264, ssRNA40, and SM-276 001, either alone or as vaccine adjuvants, induces potent immunity leading to antitumor therapeutic efficacy in several murine models. In line with these observations, it has been demonstrated that systemic TLR7 agonist injection reduces tumor progression and modulates the systemic and intratumoral immune contexture in the renal, colon and mammary carcinomas.

Protumorigenic effects of TLR7

Contrary to the therapeutic benefits of TLR7 agonists on the immune cells, several studies have suggested that TLR7 stimulation augments tumor progression. For example, in a pancreatic cancer model composed of TLR7-expressing tumor cells, the stimulation of this receptor was shown to induce an acceleration of tumor growth and reduce the expression of several antitumor molecules such as PTEN, cyclin D1 and p16, concomitantly with an increase of pro-tumoral molecules, including c-Myc, p21, p27, p53, and cyclin-B1. Apart from effects on tumor progression, TLR stimulation also impacts the efficacy of cancer treatments, particularly in the case of chemotherapy.

Local therapy of TLR7 agonist

Although it appears that TLR7 may mediate disease-promoting effects in some cancers in the setting of chronic TLR7 activation, the relevance of this finding in therapeutic applications of TLR7 agonists is unresolved. The extensive data on TLR7 agonist activity in animal cancer models is in opposition to the limited clinical efficacy of systemic TLR7 agonists observed so far: strong therapeutic results are only seen when the agonist is directly applied to the tumor, for example, by topical application on the skin, while systemic application has only led to marginal effects. Topical application allows for high tissue concentration of the agonist locally. On the contrary, systemic treatment reaches the tumor as well as nonmalignant tissues containing TLR7 expressing cells. This results in weak local agonist concentration but systemic immune activation. This causes dose-limiting side effects, which in turn prevents sufficient local TLR7 agonist concentration. Therefore, TLR7 agonists are currently mainly being developed either for local therapy or as locally applied vaccine adjuvants.

TLR7 Gene Editing Service

CRISPR/Cas9 PlatformCB at Creative Biogene is dedicated to offering comprehensive CRISPR/Cas9 gene-editing services and products for academic research, biotech research and pharmaceutical drug discovery. With deep gene editing knowledge and extensive experience in experimental operation and data processing, we help you effectively control TLR7 genes knockout/knockin/point mutation in cells or animals via CRISPR/Cas9 technology.

ServiceDetailsAlternative cell lines or animal species
TLR7 Gene Editing Cell Line GenerationgRNA design and synthesis
Transfect the cell lines you're interested
Select the high expression cells and sort monoclonal cell
Validate the knockout/knockin/point mutation of TLR7 by PCR and sequencing
Provide cryogenic preserved vials of stable cells and final reports
HEK239T, Hela, HepG2, U87, Ba/F3, CHO, MDA-MB-453, MDA-MB-231NIH3T3, T47D, Neuro2a, MCF7, RKO, K562, RAW264.7, etc.
TLR7 Gene Editing Animal Model GenerationTLR7 gene conventional knockout animals
TLR7 gene conditional knockout animals
TLR7 point mutation animals
TLR7 knockin animals
Mouse, rat, rabbit, zebrafish, C. elegans, etc.

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References

  1. Kobold S, et al. Modes of action of TLR7 agonists in cancer therapy. Immunotherapy, 2014, 6(10): 1085-1095.
  2. Dominguez-Villar M, et al. TLR7 induces anergy in human CD4+ T cells. Nature immunology, 2015, 16(1): 118.
  3. Davenne T, et al. Deoxyguanosine is a TLR7 agonist. European journal of immunology, 2020, 50(1): 56-62.
  4. Dajon M, et al. Dual roles of TLR7 in the lung cancer microenvironment. Oncoimmunology, 2015, 4(3): e991615.
For research use only. Not intended for any clinical use.

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