CXCR2-Dependent Infiltration of Tumor-Associated Neutrophils Is Linked to Enhanced CD8⁺ T Cell Effector Function and...

Triple-negative breast cancer (TNBC) is characterized by prominent neutrophil infiltration; however, its significance remains controversial. Here, we investigated the role of neutrophil chemoattractant receptors in TNBC progression and metastasis. In contrast to wild-type (WT), Fpr1^-/-, and Fpr2^-/- mice, neutrophils were almost completely absent in 4T1 tumors from Cxcr2^-/- mice, indicating a dominant role for CXCR2 in the recruitment of tumor-associated neutrophils, leading us to use Cxcr2^-/- mice for further studies. Primary tumor growth was comparable between WT and Cxcr2^-/- mice, whereas lung metastasis was significantly increased in Cxcr2^-/- mice, with reduced expression of inflammatory cytokines, chemokines and cytotoxic molecules, including granzyme B and perforin, in primary tumors and metastatic lungs of Cxcr2^-/- mice. In vitro, WT, but not Cxcr2^-/-, neutrophils enhanced CD8⁺ T cell activation, partly via ICAM-1, and directly induced tumor cell death, supporting their anti-tumor function. To assess clinical relevance, transcriptomic data were analyzed. High neutrophil infiltration combined with elevated CXCR2 expression, and to a lesser extent CXCR1 expression, was associated with improved prognosis in patients with basal-like BC that largely overlaps with TNBC. Collectively, these findings suggest that CXCR2-mediated neutrophil recruitment exerts protective, anti-tumor effects and may represent a new prognostic marker for TNBC patients.