Chen Z, Giotti B, Kaluzova M, Vallcorba MP, Rawat K, Price G, Herting CJ, Pinero G, Cristea S, Ross JL, Ackley J, Maximov V, Szulzewsky F, Thomason W, Marquez-Ropero M, Angione A, Nichols N, Tsankova NM, Michor F, Shayakhmetov DM, Gutmann DH, Tsankov AM, Hambardzumyan D. 2023. A paracrine circuit of IL-1β/IL-1R1 between myeloid and tumor cells drives genotype-dependent glioblastoma progression. The Journal of clinical investigation. 133(22). Pubmed: 37733448 DOI:10.1172/JCI163802


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-1β in MDM, which engages IL-1R1 in tumor cells, activates the NF-κB pathway, and subsequently leads to induction of monocyte chemoattractant proteins (MCPs). Thus, a feedforward paracrine circuit of IL-1β/IL-1R1 between tumors and MDM creates an interdependence driving PDGFB-driven GBM progression. Genetic loss or locally antagonizing IL-1β/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-1β, IL-1α 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-κB pathway, which drives the expression of MCPs to recruit monocytes into tumors. These results indicate local antagonism of IL-1β could be considered as an effective therapy specifically for proneural GBM.

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Franziska Michor uses the tools of theoretical evolutionary biology, applied mathematics, statistics, and computational biology to address important questions in cancer research.

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