IL1β Promotes Immune Suppression in the Tumor Microenvironment Independent of the Inflammasome and Gasdermin D

Máté Kiss, Lieselotte Vande Walle, Pedro H V Saavedra, Els Lebegge, Helena Van Damme, Aleksandar Murgaski, Junbin Qian, Manuel Ehling, Samantha Pretto, Evangelia Bolli, Jiri Keirsse, Pauline M R Bardet, Sana M Arnouk, Yvon Elkrim, Maryse Schmoetten, Jan Brughmans, Ayla Debraekeleer, Amelie Fossoul, Louis Boon, Geert RaesGeert van Loo, Diether Lambrechts, Massimiliano Mazzone, Alain Beschin, Andy Wullaert, Mohamed Lamkanfi, Jo A Van Ginderachter, Damya Laoui

Onderzoeksoutput: Article

5 Citaten (Scopus)


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+ effector T cells that subsequently activated tumor-associated macrophages. Depletion of either CD8+ T cells or macrophages abolished tumor growth inhibition in IL1β-deficient mice, demonstrating a crucial role for CD8+ 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.

Originele taal-2English
Pagina's (van-tot)309-323
Aantal pagina's15
TijdschriftCancer Immunology Research
Nummer van het tijdschrift3
Vroegere onlinedatum23 dec 2020
StatusPublished - mrt 2021

Bibliografische nota

©2020 American Association for Cancer Research.


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