The promising cancer immunotherapies should eliminate the immunosuppression occurring in the tumor microenvironment and mobilize the human immune system itself to eradicate tumor cells. Recently, toll-like receptor 9 (TLR9) agonists have been evidenced with the capability of augmenting antigen presentation and enhancing anti-tumor immunity by B and T cells. Thus, TLR9 agonists have been attracting increasing interest in its combination utilization with radiotherapy, chemotherapy, and other immunotherapeutic approaches. Creative Biolabs has successfully established an optimized Magic™ “humanized” animal platform to offer specialty manipulated TLR9 knock-in mice for our clients all over the world.
The challenge for cancer treatment is immunosuppression caused by the tumor microenvironment. The immunosuppression results in the failure of well-known immune checkpoint inhibitors anti-PD-1 antibody, anti-PD-L1 antibody, and anti-CTLA-4 antibody in some cancer patients. Thus, combinational therapy becomes the mainstream other than monotherapy.
TLR9, residing in the endoplasmatic reticulum, is a member of the TLR family which are highly conserved transmembrane proteins that recognize microbe derived molecular patterns. TLR9 is widely expressed by immune cells (such as B cells, plasmacytoid dendritic cells (pDCs), monocytes, neutrophils, T cells), non-immune cells (such as the gut, respiratory and cervical epithelia, and keratinocytes), and certain tumors (including solid tumors such as hepatocellular carcinoma, cervical squamous cell carcinoma, breast, prostate, glioma, colon and lung cancers as well as hematologic malignancies, especially B-cell lymphoma and multiple myeloma). Activation of TLR9 augments the production of inflammatory mediators.
Upon binding to the various bacterial and viral components which contain ‘unmethylated CpG DNA’, the TLR9 signal pathway is activated. This signal pathway leads to subsequent downstream activation of the MAPK and NF-κB pathways which are responsible for the proinflammatory or pro-growth of the microenvironment of the tumor. Some researchers found that binding TLR9 with its agonist CpG oligodeoxynucleotides (ODN) dramatically enhanced antitumor efficacy.
Fig.1 TLR9 receptor signaling on CpG DNA activation. (Takeshita, 2004)
Recently, targeting the signal pathways involving in oncogenesis and immunosuppression has been utilized in combining with other immunotherapies, to further improve efficacy in cancer patients. The simultaneous application of TLR9 agonists enhances the patient’s immune response and overcomes specific immunosuppression in some tumor types. With advanced technology, Creative Biolabs has successfully established the humanized TLR9 knock-in mouse model for your efficacy of potential drugs. Our professional preclinical R&D team is willing to work with you and assist you in your novel drug development. Please feel free to contact us for further discussion.
Creative Biolabs also offers other various Humanized Mouse Models you may be interested in:
Reference
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