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

Chen, Z.; Giotti, B.; Kaluzova, M.; Herting, C.; Pinero, G.; vallcorba, m. p.; Cristea, S.; Ross, J. L.; Ackley, J.; Maximov, V.; Szulzewsky, F.; Marquez-Ropero, M.; Angione, A.; Nichols, N.; Tsankkova, N.; Michor, F.; Shayakhmetov, D. M.; Gutmann, D. H.; Tsankov, A. M.; Hambardzumyan, D.

doi:10.1101/2022.04.03.486888

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bioRxiv · 10.1101/2022.04.03.486888

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

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Abstract

Monocytes and monocyte-derived macrophages (MDM) from blood circulation infiltrate and promote glioblastoma growth. Here we discover that glioma cells induce the expression of potent pro-inflammatory cytokine IL-1{beta} in MDM, which engages IL-1R1 in glioma cells, activates NF-{kappa}B pathway, and subsequently leads to the induction of monocyte chemoattractant proteins (MCPs). Thus, a feedforward paracrine circuit of IL-1{beta}/IL-1R1 between the tumors and MDM creates an interdependence driving glioblastoma progression. Locally antagonizing IL-1{beta}/IL-1R1 leads to reduced MDM infiltration, diminished tumor growth, reduced exhausted CD8+ T cells, and thereby extends the survival of tumor-bearing mice. In contrast to IL-1{beta}, IL-1a exhibits anti-tumor effects. Genetic deletion of Il1a is associated with decreased recruitment of lymphoid cells and loss of interferon (IFN) signaling in various immune populations and subsets of malignant cells. IL-1{beta} antagonism of IL-1{beta} should be considered as an effective anti-glioblastoma therapy. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=196 HEIGHT=200 SRC="FIGDIR/small/486888v1_ufig1.gif" ALT="Figure 1"> View larger version (66K): org.highwire.dtl.DTLVardef@1c99e57org.highwire.dtl.DTLVardef@1ba9d24org.highwire.dtl.DTLVardef@a2c418org.highwire.dtl.DTLVardef@1f8091c_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Chen, Z., Giotti, B., Kaluzova, M., Herting, C., Pinero, G., vallcorba, m. p., Cristea, S., Ross, J. L., Ackley, J., Maximov, V., Szulzewsky, F., Marquez-Ropero, M., Angione, A., Nichols, N., Tsankkova, N., Michor, F., Shayakhmetov, D. M., Gutmann, D. H., Tsankov, A. M., Hambardzumyan, D.. 2022-04-05. A paracrine circuit of IL-1b/IL-1R1 between myeloid and tumor cells drives glioblastoma progression. https://doi.org/10.1101/2022.04.03.486888

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