Abstract 1233: Construction and application of an immune microphysiological model for lung cancer

Abstract Tumor models are important tools for cancer research and drug development. The existing tumor models are unable to reconstruct the microphysiological processes of tumor immune responses in vivo, thus limiting their applications in the development of tumor immunological drugs and tumor immunotherapy. How to rapidly and accurately construct tumor models with a tumor immune microenvironment and an immune microphysiological system is a critical problem that urgently needs to be solved in the field of tumor immunology research and therapy. In this study, innovatively based on bio-3D printing and organ-on-a-chip technology, a lung cancer immune microphysiological system model(LCIMS) integrating the tumor area, blood vessels and lymphatic area was precisely constructed. Firstly, we screened a variety of biohydrogel materials where cells could coexist, and the hydrogel was mixed with the immune cells and fibroblastic reticular cells derived from the draining lymph nodes of lung cancer patients to generate a printable bioink. Then, lymphoid organoids with germinal centers were constructed through extrusion 3D printing. In addition, based on droplet microfluidic technology, we constructed lung cancer assembloids with intra-batch consistency and tumor microenvironment. Further, the lung cancer assembloids and lymphoid immune organoids were integrated together in an organ-on-a-chip with vascular channels, forming an immune microphysiological system with the tumor area, lymphatic area and vascular channels. In this LCIMS model, the cancer assembloids in the tumor area have similar molecular, cellular and histopathological characteristics to primary tumors, and the immune organoids in the lymphatic area have T cell and B cell regions. The results of single-cell sequencing and flow cytometry show that the organoids have similar cell subtypes and cell interaction characteristics to the patient's lymph nodes and can generate antibody responses under the stimulation of viral vaccine. In order to further explore the application value of the model in immunodrug screening, we evaluated the role of immune checkpoint inhibitor PD-1 on lung tumors. The activation of CD8+ T cells in the lymphatic area, their directed chemotaxis towards tumors, infiltration into tumors and tumor killing can be observed. In addition, the effects of CAR-T cells on cancer were tested in this model, compared to traditional tumor organoid models, the release of interleukin-6 and interferon γ in the lymphatic area can be clearly observed under the action of CAR-T cells in the model. This highlights the potential of our model to mimic the cytokine storm caused by cellular immunotherapy and its impact on tumor killing. In conclusion, the LCIMS model is a more ideal tumor immune model and has important application value in the development of tumor immunobiological drugs and the evaluation of tumor immunotherapy. Citation Format: Jianli Dai, Qianqian Wang, Junhong Li, Yang Li, Wenbo Ma, Qing Zhang, Jingyu Yang, Panglian Xu, Yanmei Zhang. Construction and application of an immune microphysiological model for lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1233.