Abstract
ObjectiveB7‐H3 is attractive for cancer immunotherapy with B7‐H3 overexpressed tumors. To explore whether B7‐H3 is an effective target for patients with bladder cancer, anti‐CD3× anti‐B7‐H3 bispecific antibodies (B7‐H3Bi‐Ab) was armed with activated T cells (ATC) to kill bladder cancer cells.MethodsHigh expressions of B7‐H3 on human bladder cancer cells were detected, including Pumc‐91 and T24 cells, and their chemotherapeutic drug‐resistant counterparts. ATC generated from healthy donors were stimulated with anti‐CD3 monoclonal antibody and interleukin‐2 (IL‐2) for 13 days. The ability of ATC armed with B7‐H3Bi‐Ab to kill bladder cancer cells was detected by flow cytometry, LDH, Elisa, and luciferase quantitative assay. Moreover, ATC generated from bladder cancer patients was armed with B7‐H3Bi‐Ab to verity the cell killing by the methods as previously described.ResultsCompared with unarmed ATC, a significant increased cytotoxicity of B7‐H3Bi‐Ab‐armed ATC against bladder cancer cells was discovered. The B7‐H3Bi‐Ab‐armed ATC secreted more IFN‐γ, TNF‐α, and expressed high levels of activation marker CD69. Interestingly, despite the presence of immunosuppression in patients and resistance in chemotherapeutic drug‐resistant cancer cell lines, B7‐H3Bi‐Ab‐armed ATC from patients with bladder cancer still showed significant cytotoxic activity against bladder cancer cells and their chemotherapeutic drug‐resistant counterparts.ConclusionB7‐H3 is an effective target for bladder cancer. B7‐H3Bi‐Ab enhances the ability of ATC to kill bladder cancer cells. B7‐H3Bi‐Ab‐armed ATC is promisingly to provide a novel strategy for current bladder cancer therapy.
Highlights
Bladder cancer is one of most common urinary tract cancers among people
According to the data provided by the literature,[21,28–30 150] ng/106 cells was chosen as the concentration of B7- H3Bi-Ab, activated T cells (ATC) mixed with OKT3 and anti-B7-H3 mAb were used as unarmed ATC controls
A significant increase was observed in IFN-γ (Figure 4A) and TNF-α (Figure 4B) secretion by B7-H 3Bi-Ab-A TC over their unarmed ATC counterpart when ATC were cultured with T24, T24/DDP, Pumc-9 1, Pumc-91/ADM
Summary
Bladder cancer is one of most common urinary tract cancers among people. In 2017, there are an estimated 79 030 cases of newly diagnosed bladder cancer and 19 870 deaths in the United States, with male morbidity and mortality four times higher than female.[1]. B7-H3, known as CD276, has up to 30% same amino acid with the B7 family members.[11] It is highly expressed in many kinds of cancer and has been shown to promote tumor development, including acute leukemia,[12] glioma,[13] hepatocellular, carcinoma,[14] breast cancer,[15] prostate cancer,[16] osteosarcoma,[17] skin melanoma,[18] and pancreatic cancer.[19]. Through the PI3K/ Akt/STAT3 signaling pathway, high expression of B7-H 3 promotes bladder cancer cells invade and metastasize.[22]. These results indicate that B7-H 3 probable be an efficacious target in the therapy of bladder cancer. Anti-CD3 antibody was conjugated with anti-B 7-H3 antibody chemically, and ATC from both healthy donors and bladder cancer patients were armed with B7-H3Bi-Ab. the ability of B7-H 3Bi-Ab-armed ATC to kill bladder cancer cell and their chemotherapeutic drug- resistant counterparts was explored. The B7-H 3Bi-Ab-a rmed ATC, with the higher expression of activation marker CD69, showed increased cytotoxicity and secreted more IFN-γ and TNF-α than unarmed ATC
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