| Autor: |
Damya Laoui, Jo A. Van Ginderachter, Mohamed Lamkanfi, Andy Wullaert, Alain Beschin, Massimiliano Mazzone, Diether Lambrechts, Geert van Loo, Geert Raes, Louis Boon, Amelie Fossoul, Ayla Debraekeleer, Jan Brughmans, Maryse Schmoetten, Yvon Elkrim, Sana M. Arnouk, Pauline M.R. Bardet, Jiri Keirsse, Evangelia Bolli, Samantha Pretto, Manuel Ehling, Junbin Qian, Aleksandar Murgaski, Helena Van Damme, Els Lebegge, Pedro H.V. Saavedra, Lieselotte Vande Walle, Máté Kiss |
| Rok vydání: |
2023 |
| DOI: |
10.1158/2326-6066.c.6550290 |
| Popis: |
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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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