IL1b is a central mediator of inflammation. Secretion of IL1b typically requires proteolytic maturation by the inflammasome and formation of membrane pores by gasdermin D (GSDMD). Emerging evidence suggests an important role for IL1b in promoting cancer progression in patients, but the underlying mechanisms are ill-defined. Here, we have shown a key role for IL1b 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 IL1b. Inflammasome-independent IL1b release promoted systemic neutrophil expansion and fostered accumulation of T-cell–suppressive neutrophils in the tumor. Moreover, IL1b was essential for neutrophil infiltration triggered by antiangiogenic therapy, thereby contributing to treatment-induced immunosuppression. Deletion of IL1b allowed intratumoral accumulation of CD8þ effector T cells that subsequently activated tumor-associated macrophages. Depletion of either CD8þ T cells or macrophages abolished tumor growth inhibition in IL1b-deficient mice, demonstrating a crucial role for CD8þ T-cell–macrophage cross-talk in the antitumor immune response. Overall, these results support a tumor-promoting role for IL1b through establishing an immunosuppressive microenvironment and show that inflammasome activation is not essential for release of this cytokine in tumors.

IL1b promotes immune suppression in the tumor microenvironment independent of the inflammasome and gasdermin D

Mazzone M.;
2021-01-01

Abstract

IL1b is a central mediator of inflammation. Secretion of IL1b typically requires proteolytic maturation by the inflammasome and formation of membrane pores by gasdermin D (GSDMD). Emerging evidence suggests an important role for IL1b in promoting cancer progression in patients, but the underlying mechanisms are ill-defined. Here, we have shown a key role for IL1b 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 IL1b. Inflammasome-independent IL1b release promoted systemic neutrophil expansion and fostered accumulation of T-cell–suppressive neutrophils in the tumor. Moreover, IL1b was essential for neutrophil infiltration triggered by antiangiogenic therapy, thereby contributing to treatment-induced immunosuppression. Deletion of IL1b allowed intratumoral accumulation of CD8þ effector T cells that subsequently activated tumor-associated macrophages. Depletion of either CD8þ T cells or macrophages abolished tumor growth inhibition in IL1b-deficient mice, demonstrating a crucial role for CD8þ T-cell–macrophage cross-talk in the antitumor immune response. Overall, these results support a tumor-promoting role for IL1b through establishing an immunosuppressive microenvironment and show that inflammasome activation is not essential for release of this cytokine in tumors.
2021
Animals
Cell Communication
Disease Models
Animal
Female
Humans
Inflammasomes
Interleukin-1beta
Intracellular Signaling Peptides and Proteins
Lymphocytes
Tumor-Infiltrating
Mice
Mice
Knockout
Neoplasms
Neutrophils
Phosphate-Binding Proteins
T-Lymphocytes
Cytotoxic
Tumor Microenvironment
Tumor-Associated Macrophages
Tumor Escape
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11699/83124
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