Glioblastoma-derived factors induce STAT3 phosphorylation and hamper human dendritic cell and Langerhans cell differentiation

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA 1031 Glioblastoma can systemically affect T cell and monocyte functions, but little is known about its direct effect on dendritic cell (DC) differentiation. Identification of glioblastoma derived immune suppressive factors and abrogation of their effects might make the tumor environment more susceptible to anti-tumor effector functions and increase the efficacy of vaccination strategies. CD34+ or CD14+ precursor cells were differentiated into interstitial DCs or Langerhans Cells (LCs) in the presence of conditioned medium of the human glioblastoma cell lines U251 and U373. Glioblastoma-conditioned medium inhibited DC and LC differentiation, resulting in maintained CD14 and reduced CD1a expression. Simultaneously, CD14+ HLA-DR- cells were induced displaying a phenotype consistent with myeloid suppressor cells (MSC). This phenotypic inhibition coincided with functional DC impairment as determined by allogeneic mixed leukocyte reaction and cytokine production profiles. Furthermore, western blot analysis showed that glioblastoma-conditioned medium induced phosphorylation of STAT3 in both DCs and LCs. Addition of cucurbitacin-I, a JAK2/STAT3 phosphorylation inhibitor, or neutralizing antibodies against interleukin (IL)-6 or transforming growth factor (TGF)-β during DC or LC differentiation reduced the levels of activated STAT3 and partially reversed the glioblastoma-induced suppression of DC or LC differentiation. In line with these data, high levels of IL-6 and TGF-β were found in the glioblastoma-conditioned media. In conclusion, the glioblastoma-derived soluble factors IL-6 and TGFβ hamper DC and LC differentiation. Targeting these factors or downstream signaling events (e.g. STAT3) may reverse their immune suppressive effects and potentially facilitate the efficacy of immunotherapies.