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

Giulia Bottai, Carlotta Raschioni, Borbála Székely, Luca Di Tommaso, A. Szász, Agnese Losurdo, B. Györffy, Balázs Ács, Rosalba Torrisi, Niki Karachaliou, Tímea Tőkés, Michele Caruso, J. Kulka, Massimo Roncalli, Armando Santoro, Alberto Mantovani, Rafael Rosell, Jorge S. Reis-Filho, Libero Santarpia

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Abstract

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 (N = 95; N = 137). In vitro, 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 (r S = 0.503; P<0.0001). Relapsing TNBC patients presented high expression of AXL (P<0.0001) and CD163 (P<0.018), but only AXL retained independent prognostic significance in multivariate analysis (relapse-free survival, P = 0.002; overall survival P = 0.001). In vitro analysis demonstrated that AXL-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.

Original languageEnglish
Article number16033
Journalnpj Breast Cancer
Volume2
Issue number1
DOIs
Publication statusPublished - dec. 14 2016

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ASJC Scopus subject areas

  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Pharmacology (medical)

Cite this

Bottai, G., Raschioni, C., Székely, B., Di Tommaso, L., Szász, A., Losurdo, A., Györffy, B., Ács, B., Torrisi, R., Karachaliou, N., Tőkés, T., Caruso, M., Kulka, J., Roncalli, M., Santoro, A., Mantovani, A., Rosell, R., Reis-Filho, J. S., & Santarpia, L. (2016). AXL-associated tumor inflammation as a poor prognostic signature in chemotherapy-treated triple-negative breast cancer patients. npj Breast Cancer, 2(1), [16033]. https://doi.org/10.1038/npjbcancer.2016.33