Abstract
BackgroundThe characterization of the immune component of the tumor microenvironment (TME) of human epidermal growth factor receptor 2 positive (HER2+) breast cancer has been limited. Molecular and spatial characterization of HER2+ TME of primary, recurrent, and metastatic breast tumors has the potential to identify immune mediated mechanisms and biomarker targets that could be used to guide selection of therapies.MethodsWe examined 15 specimens from eight patients with HER2+ breast cancer: 10 primary breast tumors (PBT), two soft tissue, one lung, and two brain metastases (BM). Using molecular profiling by bulk gene expression TME signatures, including the Tumor Inflammation Signature (TIS) and PAM50 subtyping, as well as spatial characterization of immune hot, warm, and cold regions in the stroma and tumor epithelium using 64 protein targets on the GeoMx Digital Spatial Profiler.ResultsPBT had higher infiltration of immune cells relative to metastatic sites and higher protein and gene expression of immune activation markers when compared to metastatic sites. TIS scores were lower in metastases, particularly in BM. BM also had less immune infiltration overall, but in the stromal compartment with the highest density of immune infiltration had similar levels of T cells that were less activated than PBT stromal regions suggesting immune exclusion in the tumor epithelium.ConclusionsOur findings show stromal and tumor localized immune cells in the TME are more active in primary versus metastatic disease. This suggests patients with early HER2+ breast cancer could have more benefit from immune-targeting therapies than patients with advanced disease.
Highlights
The characterization of the immune component of the tumor microenvironment (TME) of human epidermal growth factor receptor 2 positive (HER2+) breast cancer has been limited
Primary versus metastatic tumors We compared all primary breast cancer tumors to each metastatic tissue to look at differential expression of genes and protein by sample and tissue type
IO 360TM assay (IO360) signatures, Tumor Inflammation Signature (TIS) status and PAM50 subtypes from bulk tumor tissue (Fig. 1a)
Summary
The characterization of the immune component of the tumor microenvironment (TME) of human epidermal growth factor receptor 2 positive (HER2+) breast cancer has been limited. Molecular and spatial characterization of HER2+ TME of primary, recurrent, and metastatic breast tumors has the potential to identify immune mediated mechanisms and biomarker targets that could be used to guide selection of therapies. Human epidermal growth factor receptor 2 positive (HER2+) breast cancer accounts for 20–25% of all breast cancers [1, 2] These tumors were historically associated with poor prognosis [1, 2]. A better understanding of molecular biomarkers and spatial characterization of immune cells in HER2+ breast cancer environment could help for selection of combination therapies, targeting both HER2 and the immune components, that would be most effective [10, 11]. Metastatic triple negative breast cancers (TNBC) have been shown to be more immunologically quiescent than primary tumors though deep profiling of spatial characterization of immune cells in HER2+ disease has yet to be done [12,13,14]
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