Garima Kaushik, PhD, Bhavna Verma, PhD, Amy Wesa, PhD
The preclinical screening of immune-modulatory therapies suffers from the absence of models that recapitulate in vivo heterogeneous tumor microenvironment (TME). 3D tumor organoid cultures provide a model that closely mimics in situ tumor architecture and is being aggressively used to evaluate therapeutic efficacy ex vivo.
A vastly heterogenous TME impacts patient treatment response, and there is a dearth of human tumor models (2D or 3D), that mimic in vivo diversity of TME, including infiltrating immune populations. 3D organoid cultures typically contain neoplastic epithelium; however they fall short in representing tumor to tumor-infiltrating lymphocytes (TILs) interactions, limiting their ability to generate clinically relevant response to immunotherapeutics.
Addition of immune cells from unrelated donors to organoids can simulate that microenvironment but is complicated by T cell alloreactivity. Here we describe 3D patient-derived xenograft organoid (PDXO) co-cultures with matching autologous human TILs to recapitulate the tumor- specific immune response, leveraging confocal high content analysis and Luminex multiplex assays. This platform allows the evaluation and high throughput screening of novel immune targeting agents to determine impacts on patient-derived T cell function, T cell infiltration, and tumor cytotoxicity.