Spatial dissection of tumour microenvironments in gastric cancers reveals the immunosuppressive crosstalk between fibroblasts and -activated macrophages.

BACKGROUND

A spatially resolved, niche-level analysis of tumour microenvironments (TME) can provide insights into cellular interactions and their functional impacts in gastric cancers (GC).

OBJECTIVE

Our goal was to translate the spatial organisation of GC ecosystems into a functional landscape of cellular interactions involving malignant, stromal and immune cells.

DESIGN

We performed spatial transcriptomics on nine primary GC samples using the Visium platform to delineate the transcriptional landscape and dynamics of malignant, stromal and immune cells within the GC tissue architecture, highlighting cellular crosstalks and their functional consequences in the TME.

RESULTS

GC spatial transcriptomes with substantial cellular heterogeneity were delineated into six regional compartments. Specifically, the fibroblast-enriched TME upregulates epithelial-to-mesenchymal transformation and immunosuppressive response in malignant and TME cells, respectively. Cell type-specific transcriptional dynamics revealed that malignant and endothelial cells promote the cellular proliferations of TME cells, whereas the fibroblasts and immune cells are associated with procancer and anticancer immunity, respectively. Ligand-receptor analysis revealed that -expressing fibroblasts promote the tumour progression via JAK-STAT3 signalling and inflammatory response in tumour-infiltrated macrophages. fibroblasts and -activated macrophages are co-localised and their co-abundance was associated with unfavourable prognosis. We experimentally validated that fibroblasts recruit myeloid cells and stimulate activation in recruited macrophages. The development of immunosuppressive TME by fibroblasts were also validated in syngeneic mouse models.

CONCLUSION

GC spatial transcriptomes revealed functional cellular crosstalk involving multiple cell types among which the interaction between fibroblasts and -activated macrophages plays roles in establishing immune-suppressive GC TME with potential clinical relevance.