Spatial immune ecosystems govern therapeutic response in HER2-low breast cancer

HER2 low breast cancer is a complex, heterogeneous disease, and the immune factors influencing treatment outcomes are not yet fully understood. Researchers utilized single-cell spatial transcriptomics to investigate HER2 low and HER2 high tumors and examine the environmental factors that influence treatment sensitivity and resistance.

Their findings revealed an array of malignant, stromal, and immune compartments, with dendritic cells exhibiting significant remodeling in HER2 low tumors. They identified several distinct dendritic cell states, such as homeostatic cDC2, IFN-activated mature cDC, classical functional cDC2, plasmacytoid DC, and ITGAX positive monocyte-derived cDC populations.

Further analysis showed that resistant HER2 low tumors demonstrated increased segregation of tumor epithelial cells from effector immune populations, along with a higher concentration of myeloid-rich immune niches. This spatial architecture was linked to an immune-restricted environment. In a separate validation using TCGA BRCA data, elevated homeostatic cDC2 signatures predicted poor survival, while inflammatory dendritic cell signatures were associated with better outcomes.

Resistant HER2 low tumors were characterized by an increased presence of homeostatic and classical cDCs, a reduced number of IFN-activated cDCs and plasmacytoid DCs, altered tumor-myceloid T cell communication, and the formation of spatially organized resistant niches. Conversely, sensitive tumors still contained immune-intermixed niches that were enriched for antigen presentation and effector immune interactions.

In summary, these results suggest that therapeutic resistance in HER2 low breast cancer is the result of spatial remodeling of dendritic-cell states and immune architecture. The organization of dendritic cell myeloid niches may serve as a potential biomarker and therapeutic target.