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

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

  • J Clin Invest. 2023 Nov 15;133(22):e163802. doi: 10.1172/JCI163802.
Zhihong Chen 1 2 3,  Bruno Giotti 4,  Milota Kaluzova 1 2 5,  Montse Puigdelloses Vallcorba 1,  Kavita Rawat 1,  Gabrielle Price 1,  Cameron J Herting 2,  Gonzalo Pinero 1,  Simona Cristea 6 7 8 9,  James L Ross 2 10,  James Ackley 2,  Victor Maximov 2,  Frank Szulzewsky 11,  Wes Thomason 1,  Mar Marquez-Ropero 1,  Angelo Angione 1,  Noah Nichols 12,  Nadejda M Tsankova 13,  Franziska Michor 6 14 9 15 16,  Dmitry M Shayakhmetov 3 17,  David H Gutmann 18,  Alexander M Tsankov 4,  Dolores Hambardzumyan 1 2 3 12
Affiliations

Affiliations

  • 1 Department of Oncological Sciences, The Tisch Cancer Institute, Mount Sinai Icahn School of Medicine, New York, New York, USA.
  • 2 Department of Pediatrics, AFLAC Cancer and Blood Disorders Center, Children's Healthcare of Atlanta and Winship Cancer Institute, and.
  • 3 Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, USA.
  • 4 Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
  • 5 Department of Neurology, Rutgers University, New Brunswick, New Jersey, USA.
  • 6 Department of Data Science, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
  • 7 Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
  • 8 Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
  • 9 Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA.
  • 10 Emory University Department of Microbiology and Immunology, Emory Vaccine Center, Atlanta, Georgia, USA.
  • 11 Department of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
  • 12 Department of Neurosurgery and.
  • 13 Department of Pathology and Molecular and Cell-Based Medicine, Mount Sinai Icahn School of Medicine, New York, New York, USA.
  • 14 Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
  • 15 The Ludwig Center at Harvard, Boston, Massachusetts, USA.
  • 16 The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
  • 17 Lowance Center for Human Immunology and Emory Vaccine Center, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA.
  • 18 Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, USA.
PMID: 37733448 DOI: 10.1172/JCI163802
Abstract

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.

Keywords

Brain cancer; Cancer immunotherapy; Immunology; Macrophages; Oncology.

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