Abstract
Immunotherapy of bladder cancer is known to have favorable effects, although it is difficult to determine which patients will show a good response because of the different tumor microenvironments (TME). Here, we developed a bladder cancer-on-a-chip (BCOC) to mimic the TME using three-dimensional (3D) bioprinting and microfluidic technology. We fabricated a T24 and a 5637-cell line-based BCOC that also incorporated MRC-5, HUVEC, and THP-1 cells. We evaluated the effects of TME and assessed the immunologic reactions in response to different concentrations of Bacillus Calmette–Guérin (BCG) via live/dead assay and THP-1 monocytic migration, and concentrations of growth factors and cytokines. The results show that cell viability was maintained at 15% filling density in circle-shaped cell constructs at 20 μL/min microfluidic flow rate. A 3D co-culture increased the proliferation of BCOCs. We found that the appropriate time to evaluate the viability of BCOC, concentration of cytokines, and migration of monocytes was 6 h, 24 h, and three days after BGC treatment. Lastly, the immunotherapeutic effects of BCOC increased according to BCG dosage. To predict effects of immunotherapeutic agent in bladder cancer, we constructed a 3D bioprinted BCOC model. The BCOC was validated with BCG, which has been proven to be effective in the immunotherapy of bladder cancer.
Highlights
Bladder cancer is known to be responsive to immunotherapy and topical therapy with Bacillus Calmette–Guérin (BCG), which has been shown to reduce recurrences of high-risk or non-muscle invasive bladder cancer [1]
We evaluated the chemotaxis of monocytic THP-1 cells in the permeable membrane of bladder cancer-on-a-chip (BCOC) after BCG treatment according to the THP-1 cell number (Figure S6)
We found that the appropriate time to measure viability and proliferation of bladder cancer cells, secretion of cytokines, and migration of monocytes was three days, 6 h, and 24 h after BCG treatment, respectively
Summary
Reduction of tumor recurrence and progression rate via immunotherapy is one of the most important issues in the treatment of bladder cancer. Bladder cancer is known to be responsive to immunotherapy and topical therapy with Bacillus Calmette–Guérin (BCG), which has been shown to reduce recurrences of high-risk or non-muscle invasive bladder cancer [1]. Metastatic bladder cancer is a suitable candidate for experimenting with more innovative forms of immunotherapy such as new immune checkpoint inhibitors (ICIs). ICIs are monoclonal antibodies that target the inhibitory pathways of the immune system. Interaction between ICIs and their corresponding immune checkpoints increases local and systemic immune responses against tumor cells [2].
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