A paracrine circuit of IL-1β/IL-1R1 between myeloid and tumor cells drives genotype-dependent glioblastoma progression

Monocytes and monocyte-derived macrophages (MDMs) from blood circulation infiltrate glioblastoma (GBM) and promote growth. Here, we show that PDGFB-driven GBM cells induce the expression of the potent proinflammatory cytokine IL-1 beta in MDM, which engages IL-1R1 in tumor cells, activates the NF-kappa B pathway, and subsequently leads to induction of monocyte chemoattractant proteins (MCPs). Thus, a feedforward paracrine circuit of IL-1 beta/IL-1R1 between tumors and MDM creates an interdependence driving PDGFB-driven GBM progression. Genetic loss or locally antagonizing IL-1 beta/IL-1R1 leads to reduced MDM infiltration, diminished tumor growth, and reduced exhausted CD8+ T cells and thereby extends the survival of tumor-bearing mice. In contrast to IL-1 beta, IL-1 alpha exhibits antitumor effects. Genetic deletion of Il1a/b is associated with decreased recruitment of lymphoid cells and loss-of-interferon signaling in various immune populations and subsets of malignant cells and is associated with decreased survival time of PDGFB-driven tumor-bearing mice. In contrast to PDGFB-driven GBM, Ni1-silenced tumors have a constitutively active NF-kappa B pathway, which drives the expression of MCPs to recruit monocytes into tumors. These results indicate local antagonism of IL-1 beta could be considered as an effective therapy specifically for proneural GBM.

Automated summary

Monocytes and monocyte-derived macrophages infiltrate and promote the growth of glioblastoma. PDGFB-driven GBM cells induce the expression of IL-1 beta in MDM, which activates the NF-kappa B pathway and leads to the induction of monocyte chemoattractant proteins. This feedforward circuit between IL-1 beta/IL-1R1 in tumors and MDM drives PDGFB-driven GBM progression.