Fibroblast activation protein expression by stromal cells and tumor-associated macrophages in human breast cancer

Fibroblast activation protein (FAP) has long been known to be expressed in the stroma of breast cancer. However, very little is known if the magnitude of FAP expression within the stroma may have a prognostic value and reflect the heterogeneous biology of the tumor cell. An earlier study had suggested that stromal FAP expression in breast cancer was inversely proportional to prognosis. We, therefore, hypothesized that stromal FAP expression may correlate with clinicopathologic variables and may serve as an adjunct prognostic factor in breast cancer. We evaluated the expression of FAP in a panel of breast cancer tissues (n = 52) using a combination of immunostain analyses at the tissue and single-cell level using freshly frozen or freshly digested human breast tumor samples, respectively. Our results showed that FAP expression was abundantly expressed in the stroma across all breast cancer subtypes without significant correlation with clinicopathologic factors. We further identified a subset of FAP-positive (or FAP⁺) stromal cells that also expressed CD45, a pan-leukocyte marker. Using freshly dissociated human breast tumor specimens (n = 5), we demonstrated that some of these FAP⁺CD45⁺ cells were CD11b⁺CD14⁺MHC-II⁺, indicating that they were likely tumor-associated macrophages (TAMs). Although FAP ⁺CD45⁺ cells have been demonstrated in the mouse tumor stroma, our results demonstrating that human breast TAMs expressed FAP were novel and suggested that existing and future FAP-directed therapy may have dual-therapeutic benefits targeting both stromal mesenchymal cells and immune cells such as TAMs. More work is needed to explore the role of FAP as a potential targetable molecule in breast cancer treatment.