| First Author | Chen Z | Year | 2023 |
| Journal | J Clin Invest | Volume | 133 |
| Issue | 22 | PubMed ID | 37733448 |
| Mgi Jnum | J:342600 | Mgi Id | MGI:7550316 |
| Doi | 10.1172/JCI163802 | Citation | Chen Z, et al. (2023) A paracrine circuit of IL-1beta/IL-1R1 between myeloid and tumor cells drives genotype-dependent glioblastoma progression. J Clin Invest 133(22) |
| abstractText | 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-1beta in MDM, which engages IL-1R1 in tumor cells, activates the NF-kappaB pathway, and subsequently leads to induction of monocyte chemoattractant proteins (MCPs). Thus, a feedforward paracrine circuit of IL-1beta/IL-1R1 between tumors and MDM creates an interdependence driving PDGFB-driven GBM progression. Genetic loss or locally antagonizing IL-1beta/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-1beta, IL-1alpha 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, Nf1-silenced tumors have a constitutively active NF-kappaB pathway, which drives the expression of MCPs to recruit monocytes into tumors. These results indicate local antagonism of IL-1beta could be considered as an effective therapy specifically for proneural GBM. |
