Lipocalin-2 blockade reduces tumor growth and neutrophil infiltration in a mouse model for TNBC

Abstract:Breast cancer is the most common cancer type in women worldwide, and especially aggressive triple-negative breast cancer (TNBC) is a frequent cause of death in this population. Although the immune system aims to inhibit breast tumor growth, it often fails in its task due to immunosuppressive cell type presence in the breast tumor microenvironment (TME). The glycoprotein lipocalin-2 (LCN2) has been very recently suggested to contribute to the triple-negative mammary TME’s immunosuppression by fueling immunosuppressive tumor-associated neutrophils (TANs), which warrants its investigation as a potential novel (immuno)therapeutic target in TNBC. To support the translational relevance of our preclinical study, we analyzed publicly available mRNA expression datasets from (TN)BC patients. This output revealed that LCN2 expression is significantly positively correlated with expression of the myeloid cell marker CD11b/ITGAM as well as the neutrophil markers myeloperoxidase (MPO) and CD15/FUT4. High LCN2 expression was also significantly associated with decreased overall and relapse-free survival of (TN)BC patients. To evaluate the role of LCN2 inhibition, we used a 4T1-based immunocompetent and truly orthotopic (i.e. intraductal) mouse TNBC model, showing significantly reduced primary tumor growth after 2 weeks of murinized anti-LCN2 treatment compared to untreated control (p<0.001). Moreover, flow cytometric immunophenotyping showed significantly reduced TAN numbers in anti-LCN2-treated compared to untreated control primary tumors (p<0.01). These data provide a stepstone to combine anti-LCN2 with clinically relevant immunotherapy such as immune checkpoint blockade (ICB) and investigate whether LCN2 blockade can enhance ICB efficacy in complementary TNBC models, mimicking the heterogeneity in (ICB-resistant) TNBC patients.

Publication year:2024