AXL-associated tumor inflammation as a poor prognostic signature in chemotherapy-treated triple-negative breast cancer patients

• Published in: NPJ breast cancer Vol. 2; no. 1; p. 16033
• Main Authors: Bottai, Giulia, Raschioni, Carlotta, Székely, Borbála, Di Tommaso, Luca, Szász, Attila M, Losurdo, Agnese, Győrffy, Balázs, Ács, Balázs, Torrisi, Rosalba, Karachaliou, Niki, Tőkés, Tímea, Caruso, Michele, Kulka, Janina, Roncalli, Massimo, Santoro, Armando, Mantovani, Alberto, Rosell, Rafael, Reis-Filho, Jorge S, Santarpia, Libero
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 02.11.2016
• ISSN: 2374-4677; 2374-4677
• DOI: 10.1038/npjbcancer.2016.33

A subgroup of triple-negative breast cancer (TNBC) shows epithelial-to-mesenchymal transition (EMT) features, which are sustained by the interaction between cancer cells and tumor-associated macrophages (TAMs). In this study, the clinical relevance of 30 EMT-related kinases and the potential cross-talk with TAMs were investigated in a cohort of 203 TNBC patients treated with adjuvant chemotherapy. The prognostic value of the evaluated markers was validated in two independent cohorts of TNBC patients treated with adjuvant chemotherapy ( =95; =137). , we investigated the potential synergism between cancer cells and TAMs. We found that the EMT-related kinase AXL showed the highest correlation with the frequency of CD163-positive macrophages ( =0.503; <0.0001). Relapsing TNBC patients presented high expression of AXL ( <0.0001) and CD163 ( <0.018), but only AXL retained independent prognostic significance in multivariate analysis (relapse-free survival, =0.002; overall survival =0.001). analysis demonstrated that -expressing TNBC cells were able to polarize human macrophages towards an M2-like phenotype, and modulate a specific pattern of pro-tumor cytokines and chemokines. Selective AXL inhibition impaired the activity of M2-like macrophages, reducing cancer cell invasiveness, and restoring the sensitivity of breast cancer cells to chemotherapeutic drugs. These data suggest that the EMT-related kinase AXL overexpressed in cancer cells has prognostic significance, and contributes to the functional skewing of macrophage functions in TNBC. AXL inhibition may represent a novel strategy to target cancer cells, as well as tumor-promoting TAMs in TNBC.