Journal Article

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

Pinero, Gonzalo, Szulzewsky, Frank, Ross, James L., Marquez-Ropero, Mar, Cristea, Simona, Angione, Angelo, Herting, Cameron J., Gutmann, David H., Shayakhmetov, Dmitry M., Maximov, Victor, Chen, Zhihong, Giotti, Bruno, Price, Gabrielle, Rawat, Kavita, Vallcorba, Montse Puigdelloses, Nichols, Noah, Tsankova, Nadejda M., Michor, Franziska, Kaluzova, Milota, Tsankov, Alexander M., Hambardzumyan, Dolores, Ackley, James, Thomason, Wes

2023

Overview

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.

• Publisher: American Society for Clinical Investigation
• Subject: Animals / Antitumor activity / Biomedical research / Blood circulation / Bone marrow / Brain cancer / CD8 antigen / Cytokines / Genes / Genotype / Genotypes / Glioblastoma / Glioblastoma - metabolism / Glioblastoma - pathology / Humans / Immunology / Inflammation / Interleukin 1 receptors / Interleukin-1beta - metabolism / Interleukins / Lymphocytes / Lymphocytes T / Lymphoid cells / Macrophages / Macrophages - metabolism / Medical prognosis / Metastases / Mice / Monocytes / NF-kappa B - genetics / NF-kappa B - metabolism / NF-κB protein / Oncology / Paracrine Communication / Paracrine signalling / Patients / Proto-Oncogene Proteins c-sis - metabolism / Receptors, Interleukin-1 - metabolism / Receptors, Interleukin-1 Type I - metabolism / Tumor cells / Tumors