Abstract:
The tumor microenvironment (TME) plays a crucial role in tumor growth and treatment response. Traditional animal models fail to accurately replicate the human TME, carcinogenesis, immune responses, metabolism, pathophysiology, and adverse events, limiting their usefulness in studying cancer development and therapies, especially those involving the immune system. To address these limitations, this thesis aimed to develop microphysiological tumor-on-chip models that closely mimic human TME and immune responses, enabling detailed studies of cancer-TME interactions and immunotherapy responses. The first part of the work focused on the development and utilization of a tumor-on-chip model for evaluating the efficacy and safety of chimeric antigen receptor (CAR)-T cell immunotherapy in a solid TME. This model examined CAR-T cell responses in relation to target antigen levels, tumor size, and TME components, such as endothelial barriers and macrophages. Excessive antitumor response by CAR-T cells was captured through the monitoring of inflammatory cytokine release kinetics, which allowed the testing of acute safety intervention strategy on the chip. This model offers a rapid and adaptable platform for comparing different CAR-T cell products and exploring strategies to overcome TME barriers. The second part of the work focused on establishing a breast cancer-on-chip model to recreate the breast TME for studying interactions between breast tumors and white adipose tissue (WAT). This platform uniquely integrated breast cancer spheroids or patient-derived organoids central to the surrounding WAT-associated cells in a perfusable microfluidic chamber, allowing long-term co-culture that lasted for up to two weeks. Using this model, it was demonstrated that the presence of breast cancer increased lipolytic activity in adipocytes and that WAT increased lipid accumulation and promoted growth of breast cancer cells. Notably, WAT protected breast cancer cells from the chemotherapeutic agent daunorubicin, highlighting the TME's critical role in modulating cancer treatment efficacy. Overall, this thesis established tumor-on-chip models to study tumor-TME interactions and cancer immunotherapies, laying the foundation for mechanistic research and clinical translation of therapies designed to overcome TME barriers.
organ-on-chip