| First Author | Kiss M | Year | 2021 |
| Journal | Cancer Immunol Res | Volume | 9 |
| Issue | 3 | Pages | 309-323 |
| PubMed ID | 33361087 | Mgi Jnum | J:327023 |
| Mgi Id | MGI:6879207 | Doi | 10.1158/2326-6066.CIR-20-0431 |
| Citation | Kiss M, et al. (2021) IL1beta Promotes Immune Suppression in the Tumor Microenvironment Independent of the Inflammasome and Gasdermin D. Cancer Immunol Res 9(3):309-323 |
| abstractText | IL1beta is a central mediator of inflammation. Secretion of IL1beta typically requires proteolytic maturation by the inflammasome and formation of membrane pores by gasdermin D (GSDMD). Emerging evidence suggests an important role for IL1beta in promoting cancer progression in patients, but the underlying mechanisms are ill-defined. Here, we have shown a key role for IL1beta 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 IL1beta. Inflammasome-independent IL1beta release promoted systemic neutrophil expansion and fostered accumulation of T-cell-suppressive neutrophils in the tumor. Moreover, IL1beta was essential for neutrophil infiltration triggered by antiangiogenic therapy, thereby contributing to treatment-induced immunosuppression. Deletion of IL1beta 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 IL1beta-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 IL1beta through establishing an immunosuppressive microenvironment and show that inflammasome activation is not essential for release of this cytokine in tumors. |
