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B7-H3 (or CD276) belongs to a family of immune modulators that includes programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1, also known as CD274 or B7-H1) and has been associated with tumor immunosuppression and decreased survival of cancer patients. Induced on antigen presenting cells, B7-H3 plays a crucial role in the inhibition of T cell function. Most importantly, B7-H3 is highly overexpressed on many human solid cancers and often correlates with both negative prognosis and poor clinical outcomes in patients. Accumulating evidence shows that B7-H3 orchestrates antitumor immunity by providing co-stimulatory and co-inhibitory signals under different cancer contexts. Challenges remain to identify the receptor(s) of B7-H3 and better elucidate the role of the B7-H3 pathway in immune responses and tumor evasion. With a preferential expression on tumor cells, B7-H3 is an ideal target for cancer immunotherapy.
Knocking down its expression or inhibiting B7-H3 decreases the growth of many types of cancer cells in vivo and in vitro. In addition, the adhesion, migration, invasion, and metastasis of cancer cells are affected by B7-H3 expression levels. An increasing number of studies support a pro-oncogenic role for B7-H3 in various types of cancer that is independent of its immune function. B7-H3 seems to act upstream from signal transduction pathways, such as the PI3K/Akt/mTOR and JAK/STAT pathways, to induce proliferative and anti-apoptotic mechanisms. Moreover, B7-H3 modulates the expression of cytokines and metalloproteinases involved in metastasis such as MMP-2, IL-8, TIMP-1, and TIMP-2 through the PI3K/Akt/mTOR and NF-kB pathways. B7-H3 expression was also recently shown to inhibit the transcription factor NRF2, resulting in increased reactive oxygen species (ROS) and HIF1a levels, thereby inducing aerobic glycolysis and leading to tumor growth. B7-H3 also promotes resistance to cancer drugs. A growing number of studies suggest that inhibition or reduced expression of B7-H3 increases the response of tumor cells to drugs that target DNA replication, alkylating agents, and inhibitors of PI3K/Akt/mTOR and Ras/Raf/MEK signaling. This further supports B7-H3 as a target in anticancer therapy, alone or in combination with other existing therapeutic modalities.
Figure 1. Schematic Overview of B7-H3 Signaling in Tumor Cells. (Flem-Karlsen K, et al., 2018)
The scientific community has explored B7-H3 as a therapeutic role in cancer in multiple ways. Enoblituzumab (MGA271), a mAb reactive to cancer-associated B7-H3 showed enhanced anti-tumor function through potent ADCC against a broad range of tumor cell types. Preliminary results of the dose escalation study suggest that as a monotherapy, the Fc-enhanced mAb Enoblitzumab, demonstrates anti-tumor activity in several tumor types and modulates T cells through increasing the T cell repertoire clonality in the peripheral blood of patients following treatment.
Recent studies have shown that the combination of multiple chemotherapeutics with checkpoint inhibitors display great synergistic effects that enhanced the prospects of its full utilization in standard clinical practice. Based on a few preclinical animal studies, the combination of B7-H3 blockade and chemotherapy looks promising. Indeed, the silencing of B7-H3 by shRNA in a histiocytic lymphoma derived human cell line, U937, in combination with the anti-neoplastic drug Ara-C led to 80% tumor reduction compared to the 40% inhibition observed in wild-type U937 cells combined with Ara-C in a mouse xenograft model. Similarly, shRNA silencing of B7-H3 in a murine model of breast cancer, combined with the chemotherapeutic Paclitaxel, showed about 80% reduction in tumor growth compared to the untreated wild-type cells. These studies provide a rationale for the potential synergistic effects between B7-H3 blockade and chemotherapy or targeted therapy for patients with multiple cancers.
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 CD276 genes knockout/knockin/point mutation in cells or animals via CRISPR/Cas9 technology.
|Service||Details||Alternative cell lines or animal species|
|CD276 Gene Editing Cell Line Generation||gRNA 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 CD276 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.|
|CD276 Gene Editing Animal Model Generation||CD276 gene conventional knockout animals|
CD276 gene conditional knockout animals
CD276 point mutation animals
CD276 knockin animals
|Mouse, rat, rabbit, zebrafish, C. elegans, etc.|
|CATALOG NO.||PRODUCT NAME||PRODUCT TYPE||INQUIRY|
|CLKO-0133||CD276 KO Cell Lysate-HeLa||Knockout Cell Lysate||Inquiry|
|CLKO-0967||CD276 KO Cell Lysate-HEK293T||Knockout Cell Lysate||Inquiry|
|CSC-RT0115||CD276 Knockout Cell Line-MG63||Pre-Made Knockout Cell Line||Inquiry|
|CSC-RT0134||CD276 Knockout Cell Line-HeLa||Pre-Made Knockout Cell Line||Inquiry|
|CSC-RT0627||Human CD276 Knockout Cell Line-HeLa||Pre-Made Knockout Cell Line||Inquiry|