TIvatar efficiently recapitulates endogenous cancer immunotherapy responses in vitro 2512

Abstract Description Tumor organoids are used to study the mechanisms inherent to tumor cells and their microenvironment; however, organoids do not accurately replicate the tumor immune microenvironment (TIME), essential to bridging preclinical immunotherapy (IT) discovery with clinical trial success. To address this issue, we developed TIvatar, a high throughput in vitro model that preserves the cellular diversity of the TIME in tumor-mimetic scaffolds, allowing us to screen IT responses in both murine preclinical models and primary human tumors via longitudinal imaging, cytokine analysis and flow cytometry. We demonstrate that, in contrast to organoids, TIvatar supports CD8+ T cell phenotypic changes in response to immune checkpoint inhibition (ICI) and accurately reflects in vivo tumor susceptibility to various IT modalities, including cancer vaccines and cytokine therapies. Additionally, we identified cellular mediators of novel ITs by selectively depleting immune and stromal cell populations in TIvatar cultures. Finally, we identified specific immune features of resected primary ovarian tumors that positively correlated with their susceptibility to ICI in TIvatar. Here, we established TIvatar as a novel platform to functionally interrogate tumor immunity and the mechanisms behind IT responses in both preclinical models and primary human tumor resections. The TIvatar platform will likely bridge the gap in IT assessment between preclinical studies and clinical implementation. Funding Sources Supported by NIH/NCI R01-CA253248; AbbVie, Inc.; UChicago Medicine Comprehensive Cancer Center (UCCCC) Translational Group of Research Excellence (TGRE) Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)