期刊
CANCER IMMUNOLOGY RESEARCH
卷 9, 期 3, 页码 309-323出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2326-6066.CIR-20-0431
关键词
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资金
- Research Foundation -Flanders (FWO) [1S23316N]
- Kom op tegen Kanker (Stand up to Cancer)
- FWO [1S67419N, 1S16718N, 1S24117N, 1S68420N, 1154720N, 1S78120N, 12Z1820N, 3G.0447.18]
- Kom op tegen Kanker [STIVLK2017000401]
- Vrije Universiteit Brussel
- FWO-NAFOSTED [G0F3616N]
IL-1β plays a crucial role in promoting tumor progression and establishing an immunosuppressive microenvironment. The release of IL-1β may not necessarily require inflammasome activation. The crosstalk between CD8(+) T cells and macrophages is essential for anti-tumor immune response.
IL1 beta is a central mediator of inflammation. Secretion of IL1 beta typically requires proteolytic maturation by the inflammasome and formation of membrane pores by gasdermin D (GSDMD). Emerging evidence suggests an important role for IL1 beta in promoting cancer progression in patients, but the underlying mechanisms are ill-defined. Here, we have shown a key role for IL1 beta 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 IL1 beta. Inflammasome-independent IL1 beta release promoted systemic neutrophil expansion and fostered accumulation of T-cell-suppressive neutrophils in the tumor. Moreover, IL1 beta was essential for neutrophil infiltration triggered by antiangiogenic therapy, thereby contributing to treatment-induced immunosuppression. Deletion of IL1 beta allowed intratumoral accumulation of CD8(+) effectorT cells that subsequently activated tumor-associated macrophages. Depletion of either CD8(+) T cells or macrophages abolished tumor growth inhibition in IL1 beta-deficient mice, demonstrating a crucial role for CD8(+) T-cell-macrophage cross-talk in the antitumor immune response. Overall, these results support a tumor-romoting role for IL1 beta through establishing an immunosuppressive microenvironment and show that inflammasome activation is not essential for release of this cytokine in tumors.
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