Tumor-associated neutrophils are a negative prognostic factor in luminal breast cancers lacking immunosuppressive macrophage recruitment

Background: Tumor-associated neutrophils (TAN) are important modulators of the tumor microenvironment with opposing functions which can promote and inhibit tumor progression. The prognostic role of TANs in the luminal breast cancer subtype is unclear. Methods: A total of 144 patients were treated for early-stage hormone receptor positive breast cancer as part of an Accelerated Partial Breast Irradiation (APBI) phase II trial. Resection samples from multiple locations were processed into tissue microarrays and sections thereof immunohistochemically stained for CD66b+ neutrophils. CD66b+ neutrophil density was measured separately in the stromal and intraepithelial compartment. Results: High stromal and intraepithelial CD66b+ TAN density was a negative prognostic factor in central tumor samples. In addition, neutrophil density in adjacent normal breast tissue and lymph node samples also correlated with reduced disease-free survival. TAN density correlated with CD163+ M2-like tumor-associated macrophage (TAM) density, which we analyzed in a previous study. A combined analysis of TAM and TAN density revealed that TANs were only prognostically relevant in tumors with an elevated M1/M2 TAM ratio, while there was no impact on patient outcome in tumors with a low M1/M2 ratio. Conclusions: In conclusion, numerous CD66b+ neutrophils in tumor tissue, normal breast tissue and lymph nodes are a negative prognostic factor in early-stage luminal breast cancer. TAN recruitment might act as a compensatory mechanism of immunoevasion and disease progression in tumors which are unable to sufficiently attract and polarize TAMs.