An Integrated Spatial Atlas of the Tumor Micro-environment of Early Non-Small Cell Lung Cancer
Immunotherapy targeting the PD-1/PD-L1 axis has revolutionized treatment of advanced non-small cell lung cancer (NSCLC), and recent studies on its use in the early setting appear promising. However, only a minority of unselected patients benefit from this treatment, and the molecular mechanisms that determine response are not yet fully known. Recently, single-cell omics technologies have led to great advances in the understanding the differences in the tumor micro-environment (TME) of responders and non-responders to immunotherapy. Unfortunately, these techniques destroy the tissue organization during dissociation and cannot capture the spatial relationship between cells which is critical to studying cell interactions inside the TME. The goal of the proposed PhD project is to build on the established single-cell expertise of the research lab by applying novel spatial omics technologies to create an integrated spatial atlas of the TME in human early NSCLC. Several consecutive tissue slices will be cut from each treatment-naive tumor resection sample so that every slice can be processed by a different spatial omics technology: transcriptomics (Molecular Cartography, BGI Stereo-seq), proteomics (Akoya PhenoCycler) or metabolomics (MALDI, DESI). The major computational challenges involved in the integration of these technologies are the alignment of microscopy images and the combining of molecular data at different resolutions, in addition to correction for batch effects when analyzing multiple samples – none of which are solved problems in the literature. As such, a critical part of the proposed project will be to adapt existing single-cell computational methods to the spatial setting, and to develop new bioinformatics tools where necessary. Combining these spatial data with the lab’s prior expertise and single-cell datasets will allow for a detailed characterization of immune and stromal cell states previously unattainable in a spatial setting. This integrated spatial cell atlas of early NSCLC will lead to new insights into the TME and its role in response to immunotherapy.