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

Author:

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

Abstract

SummaryMonocytes 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-1β in MDM, which engages IL-1R1 in glioma cells, activates NF-κB pathway, and subsequently leads to the induction of monocyte chemoattractant proteins (MCPs). Thus, a feedforward paracrine circuit of IL-1β/IL-1R1 between the tumors and MDM creates an interdependence driving glioblastoma progression. Locally antagonizing IL-1β/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-1β, IL-1a exhibits anti-tumor effects. Genetic deletion ofIl1ais associated with decreased recruitment of lymphoid cells and loss of interferon (IFN) signaling in various immune populations and subsets of malignant cells. IL-1β antagonism of IL-1β should be considered as an effective anti-glioblastoma therapy.Graphical Abstract

Publisher

Cold Spring Harbor Laboratory

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