NEW YORK – A team from the UK, Switzerland, and Canada has tracked down several recurrent features in microenvironment samples associated with breast tumors, including tumor microenvironment (TME) patterns that appeared to coincide with specific breast cancer subtypes and survival outcomes.
"Given the intimate link between structure and function, it follows that these multicellular structures offer a window on the functional state of the TME, and their associations with outcome suggest their characterization could be useful for patient stratification," co-senior and co-corresponding authors Raza Ali, a researcher affiliated with the University of Cambridge, the University of Zurich, and Addenbrookes Hospital, Carlos Caldas, a University of Cambridge researcher, and their colleagues wrote in Nature Genetics on Monday.
For their study, the researchers relied on imaging mass cytometry, immunohistochemistry, spatial analysis, and other approaches to get a multidimensional look at pretreatment formalin-fixed paraffin-embedded microenvironment tissue microarray samples representing 693 breast cancer cases, setting the TME structures in these samples against available survival data and corresponding tumor genomic profiles, including array-based expression profiles, comparative genomic hybridization, and/or targeted gene sequencing data.
"In our study, high-dimensional imaging revealed how the specialized cells of the breast [tumor microenvironment] organize in space, how this organization varies across tumors, and how various structures impact clinical outcomes," the authors wrote. "Our approach enables a deeper understanding of structural immunity in tumors and may help identify patients likely to respond to therapies that function by perturbing spatial organization of the [tumor microenvironment]."
Along with key cell types in the sample set, the team described dozens of epithelial and non-epithelial cell phenotypes, focusing on the non-epithelial set to define recurrent TME structures, including structures that appeared to coincide with specific breast cancer subtypes, immune response features, and/or tumor genome changes.
"We identified 10 recurrent TME structures that varied by vascular content, stromal quiescence versus activation, and leukocyte composition," the authors reported. "These TME structures had distinct enrichment patterns among breast cancer subtypes, and some were associated with genomic profiles indicative of immune escape."
When it came to cases from the estrogen receptor-positive breast cancer subtype, for example, the investigators identified four TME structures, including three structures associated with reduced survival outcomes. One of the poor prognostic structures, called a "suppressed expansion" TME, was marked by cellular diversity and dysfunctional T-cell and regulatory T-cell features. That type of TME tended to occur in combination with proliferating cells and in the presence of tumor mutations affecting the BRCA1 and CASP8 genes.
While BRCA1 alterations have been linked to high levels of somatic mutation, owing to related homologous recombination-mediated double-strand break repair problems, the team explained, prior studies have suggested that CASP8 mutations can contribute to immune escape hinting that the immune response prompted by BRCA1 mutations may be offset by CASP8 alterations that help the tumor cells survive, contributing to the poor outcomes associated with corresponding TME structures.
"The curated data are available as a resource that, together with our experimental and analytical approach, pave the way for future work to understand principles of spatial organization in cancer tissues," the authors wrote, adding that "[f]uture analyses of high-resolution sequencing data with temporal inference of mutations, together with high-dimensional imaging of the TME, should enable deeper interrogation of this dynamic and may reveal the extent to which the selection of driver alterations is sensitive to TME context."