Ependymoma (EPN) in childhood is a brain tumor with substantial mortality. Inflammatory response has been identified as a molecular signature of high-risk Group A EPN. To better understand the biology of this phenotype and aid therapeutic development, transcriptomic data from Group A and B EPN patient tumor samples, and additional malignant and normal brain data, were analyzed to identify the mechanism underlying EPN Group A inflammation. Enrichment of interleukin-6 (IL-6) and STAT3 pathway genes were found to distinguish Group A EPN from Group B EPN and other brain tumors, implicating an IL-6 activation of STAT3 mechanism. EPN tumor cell growth was shown to be dependent on STAT3 activity, as demonstrated using shRNA knockdown and pharmacological inhibition of STAT3 that blocked proliferation and induced apoptosis. The inflammatory factors secreted by EPN tumor cells were shown to reprogram myeloid cells and this paracrine effect was characterized by a significant increase in pSTAT3 and IL-8 secretion. Myeloid polarization was shown to be dependent on tumor secretion of IL-6, and these effects could be reversed using IL-6 neutralizing antibody or IL-6 receptor-targeted therapeutic antibody tocilizumab. Polarized myeloid cell production of IL-8 drove un-polarized myeloid cells to up-regulate CD163 and to produce a number of pro-inflammatory cytokines. Collectively, these findings indicate that constitutive IL-6/STAT3 pathway activation is important in driving tumor growth and inflammatory crosstalk with myeloid cells within the Group A EPN microenvironment. Effective design of Group A-targeted therapy for children with EPN may require reversal of this potentially immunosuppressive and pro-tumor pathway.
- Received March 3, 2015.
- Accepted May 3, 2015.
- Copyright © 2015, American Association for Cancer Research.