GM-CSF downregulates type I IFN responses in glioblastoma-associated monocytes

Glioblastoma (GB) is the most aggressive type of brain cancer with a devastating prognosis. Myeloid cells, especially monocytes and macrophages, comprise the majority of immune cells within the GB tumour microenvironment, where they contribute to the development of an immunosuppressive milieu hindering potential anti-tumour immune responses. Type I IFNs usually facilitate a pro-inflammatory shift in monocytes and macrophages and allow for anti-tumour functions. Using RNA sequencing, we observed that type I IFN-stimulated genes (ISGs) are globally downregulated in primary human monocytes, but not microglia, co-cultured with GB cells both upon direct cell-cell contact and upon the exchange of soluble factors. Surprisingly, the reduction of type I IFN responses did not result from changes in interferon-α/β-receptor availability and activation. Instead, we identified GM-CSF as a critical, GB cell-derived factor, which decreased ISG expression in monocytes at extremely low concentrations via induction of the TGF-β signalling pathway. In line, type I IFN response gene expression and GM-CSF activity in human GB biopsies appeared to be mutually exclusive. Specifically, active GM-CSF signalling appeared to inhibit ISG expression in the same cell as well as in neighbouring monocyte-derived macrophages, which resulted in lower T cell recruitment. In conclusion, our data provide evidence for a so far unknown GM-CSF- and TGF-β-dependent type I IFN inhibitory mechanism in GB with potential implications for future therapeutic approaches.