Establishment of spatial transcriptomics assay to find the mechanism of immune therapy against tumors

Intra-tumor heterogeneity is one of the biggest challenges in cancer treatment today, not only on cell types and functions, but also on the spatial pattern of immune cells within the tumor tissue. While most of  single-cell RNA sequencing technologies enable the exploration of gene expression heterogeneity at the single cell level, they cannot provide spatial information within the tumor for researchers to map the whole transcriptome with morphological context. Spatial transcriptomics is an in situ capturing technique, which profiles gene expression at the RNA level, while preserving the spatial information of histological tissue sections. We undertook to develop a spatial transcriptomics assay through a series of validation experiments, to find the mechanism of immune therapy against tumors.

In this study, we established a reliable system for spatial transcriptomics assay to elucidate the mechanism of anti-PD1 treatment in the mouse syngeneic model MC38. Using this system, we  constructed gene expression spatial patterns of mouse tumor cells and immune cells, including periphery and center of tumor cell, immune-cell enrichment areas and tumor cells surrounding immune cells. Furthermore, we explored the cell-cell interactions in which the mouse tumor cells directly interact with adjacent non-tumor cells, for example macrophages. Using this system, we attempted to find the mechanism of anti-PD-1 treatment against tumors by comparing the spatial transcriptome profiles changed after treatment with anti-PD-1 or isotype control in mouse colorectal cancer models. Interestingly, changes in both gene level and spatial level were observed, and this will help us to reveal how immune therapy may disrupt the complex ecosystem.

In summary, we have optimized and established a reliable system for spatial transcriptomics analysis, to dissect the complicated changes of the tumor microenvironment after immune checkpoint blocker treatment. Spatial RNA-seq technology can be a powerful method to help find the
potential mechanism after immunotherapy and to identify the possible therapeutic targets.

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