Back to Search
Start Over
IL1β Promotes Immune Suppression in the Tumor Microenvironment Independent of the Inflammasome and Gasdermin D.
- Source :
-
Cancer immunology research [Cancer Immunol Res] 2021 Mar; Vol. 9 (3), pp. 309-323. Date of Electronic Publication: 2020 Dec 23. - Publication Year :
- 2021
-
Abstract
- IL1β is a central mediator of inflammation. Secretion of IL1β typically requires proteolytic maturation by the inflammasome and formation of membrane pores by gasdermin D (GSDMD). Emerging evidence suggests an important role for IL1β in promoting cancer progression in patients, but the underlying mechanisms are ill-defined. Here, we have shown a key role for IL1β in driving tumor progression in two distinct mouse tumor models. Notably, activation of the inflammasome, caspase-8, as well as the pore-forming proteins GSDMD and mixed lineage kinase domain-like protein in the host were dispensable for the release of intratumoral bioactive IL1β. Inflammasome-independent IL1β release promoted systemic neutrophil expansion and fostered accumulation of T-cell-suppressive neutrophils in the tumor. Moreover, IL1β was essential for neutrophil infiltration triggered by antiangiogenic therapy, thereby contributing to treatment-induced immunosuppression. Deletion of IL1β allowed intratumoral accumulation of CD8 <superscript>+</superscript> effector T cells that subsequently activated tumor-associated macrophages. Depletion of either CD8 <superscript>+</superscript> T cells or macrophages abolished tumor growth inhibition in IL1β-deficient mice, demonstrating a crucial role for CD8 <superscript>+</superscript> T-cell-macrophage cross-talk in the antitumor immune response. Overall, these results support a tumor-promoting role for IL1β through establishing an immunosuppressive microenvironment and show that inflammasome activation is not essential for release of this cytokine in tumors.<br /> (©2020 American Association for Cancer Research.)
- Subjects :
- Animals
Cell Communication immunology
Disease Models, Animal
Female
Humans
Inflammasomes immunology
Inflammasomes metabolism
Interleukin-1beta genetics
Intracellular Signaling Peptides and Proteins genetics
Intracellular Signaling Peptides and Proteins metabolism
Lymphocytes, Tumor-Infiltrating immunology
Mice
Mice, Knockout
Neoplasms pathology
Neutrophils metabolism
Phosphate-Binding Proteins genetics
Phosphate-Binding Proteins metabolism
T-Lymphocytes, Cytotoxic immunology
Tumor-Associated Macrophages immunology
Interleukin-1beta metabolism
Neoplasms immunology
Neutrophils immunology
Tumor Escape
Tumor Microenvironment immunology
Subjects
Details
- Language :
- English
- ISSN :
- 2326-6074
- Volume :
- 9
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Cancer immunology research
- Publication Type :
- Academic Journal
- Accession number :
- 33361087
- Full Text :
- https://doi.org/10.1158/2326-6066.CIR-20-0431