A Novel Gene Signature predicts immune infiltration phenotypes in humanized Patient Derived Xenograft Models
The Tumor Microenvironment (TME) can orchestrate tumor progression, metastasis, and the development of therapeutic resistance through a variety of mechanisms. Specifically, TME can impair response to therapy by modulating evasion of tumor cells from immune surveillance. Improving our understanding of how different immune cell populations shape the TME and impact therapeutic response becomes crucial to improving patient outcomes.
When an immunotherapy test agent reaches pre-clinical stages, the use of clinically and biologically relevant models is crucial. However, current preclinical models may suffer from the lack of a comprehensive characterization of the TME of the selected cancer models.
To overcome this limitation, Champions Oncology leveraged transcriptomic data from its proprietary bank of TumorGraft® models to develop a signature to predict immune infiltration. This signature was validated by confirming the predicted immune infiltration phenotype through histological analysis of PDX models grown in humanized mice, harboring a fully reconstituted human immune system.
Among the variety of pre-clinical models, patient-derived xenograft (PDX) models are recognized as an accurate and clinically relevant system for pre-clinical studies1,2. For these reasons, Champions Oncology built the pre-clinical research on a deeply characterized PDX bank. The characterization through multi-omic datasets includes cutting-edge technologies such as next-generation sequencing (WES and RNAseq) proteomics, phosphor-proteomics, kinase activity, and patient’s historical treatment data.
To identify a molecular signature predictive of immune infiltration, we analyzed Champions PDX by leveraging proprietary and public computational methods. Among the different computational tools, we leveraged xCell 3 to perform cell type enrichment analysis on 64 immune and stroma cell types. In parallel, mice were humanized using different strategies4 and PDXs were implanted in hosts harboring a fully reconstituted human immune system.