Integrating multiplexed imaging and multiscale modeling identifies tumor phenotype conversion as a critical component of therapeutic T cell efficacy

Cancer progression is a complex process involving interactions that unfold across molecular, cellular, and tissue scales. These multiscale interactions have been difficult to measure and to simulate. Here, we integrated CODEX multiplexed tissue imaging with multiscale modeling software to model key action points that influence the outcome of T cell therapies with cancer. The initial phenotype of therapeutic T cells influences the ability of T cells to convert tumor cells to an inflammatory, anti-proliferative phenotype. This T cell phenotype could be preserved by structural reprogramming to facilitate continual tumor phenotype conversion and killing. One takeaway is that controlling the rate of cancer phenotype conversion is critical for control of tumor growth. The results suggest new design criteria and patient selection metrics for T cell therapies, call for a rethinking of T cell therapeutic implementation, and provide a foundation for synergistically integrating multiplexed imaging data with multiscale modeling of the cancer-immune interface. A record of this paper’s transparent peer review process is included in the supplemental information. [Display omitted] •T cells’ early induction of non-proliferative tumor phenotype crucial for efficacy•Multiscale modeling is built and integrated with multiscale, spatial-omics data•Distinct spatial environments in tumors are key for T cell phenotype preservation•Modeling adds multiscale spatial dynamics, prompting new spatial-omics experiments Hickey et al. integrated multiplexed CODEX tissue imaging with multiscale modeling, showing that initial T cell phenotype affects tumor conversion to anti-proliferative state, critical for controlling growth rate. Structural reprogramming also maintains T cell phenotype, aiding in continual tumor killing. Findings stress the importance of back-and-forth modeling and spatial-omics, guiding new T cell treatment designs.