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Mapping immune microlandscapes in breast cancer

Spatial immune microlandscapes in triple-negative breast cancer (TNBC) have been investigated in a recent paper, published in Nature Communications. The research used high-plex quantitative digital spatial profiling to map the spatial immunobiology of TNBC, potentially identifying clinically actionable immune biomarkers.

Immune response impacts therapeutic response

Over the past decade, it has been established that host-tumour immune responses can predict clinical outcomes and therapeutic responses in TNBC patients. Most notably, the expression of programmed death-ligand 1 (PD-L1) has been associated with improved outcomes and better responses to the immune checkpoint inhibitors (ICIs) pembrolizumab and atezolizumab.

However, some recent concerns about the use of ICIs in TNBC have also been raised. In patients with metastatic TNBC, the clinical benefit of ICIs has been modest – leading to the voluntary withdrawal of atezolizumab from the US market. As well as this, PD-L1 status was found not to be predictive of pembrolizumab response in early-stage cancers, despite the ICI being approved in combination with chemotherapy for this setting.

These findings highlight the need for optimised tissue-based biomarkers for immunotherapy selection in TNBC, particularly as research is now expanding past the PD-L1 axis. For example, tumour-infiltrating lymphocytes have been associated with improved survival and the importance of tumoral immune microenvironments has also been recognised.

Spatial profiling of the tumour microenvironment

Addressing the need for optimised immune biomarkers, researchers from the Mayo Clinic used the GeoMx™ Digital Spatial Profiling (DSP) platform (NanoString) to gain a more detailed understanding of the tumour microenvironment in TNBC. DSP utilises UV-photocleavable oligonucleotide-conjugated antibodies bound to regions of interest to provide quantification and localisation of targets with high multiplexing.

In the study, the DSP platform was used to map and quantify immune proteins in two cohorts of therapy naïve TNBC patients. The aim of this was to achieve a comprehensive immune microenvironment characterisation, including quantitation and localisation of cell types, target proteins and immune cells.

Revealing a spatial prognosis

In the two TNBC cohorts, dozens of immune proteins were quantified and mapped to determine the influence of spatial context on immune microenvironments. Substantial differences were found between the intraepithelial segments and the adjacent stromal immune microenvironments, demonstrating that spatial context influences immune protein microenvironments. Immune proteins related to antigen presentation in the intraepithelial segment (HLA-DR, CD11C and CD40) were also found to be independently prognostic of TNBC patient outcomes.

The authors discussed some of the limitations of DSP, stating that the platform could not achieve single-cell resolution or protein co-expression in the same cell. Despite this, the platform still offered high sensitivity, resolution and spatial capabilities that revealed unseen, clinically relevant insights into immune protein architecture. The authors concluded by saying, “These data provide insight into immune-based therapies and their companion diagnostic assays and complement existing immune-based prognosticators in TNBC… to optimize patient selection for immune-based or other therapies”.