Abstract 5330: Intestine-specific homeobox edits macrophage polarization in the disease microenvironment by activating inflammasome activity

Abstract

Abstract Inflammasome activity has a pivotal role in the innate immune system, highlighting its importance in the development of various inflammatory diseases, including cancers. However, the specific impact of inflammasome-produced cytokines from tumor cells on disease progression remains uncertain. In this study, we show that the expression levels of inflammasome-related genes (NLRP1 and NLRP3), combined with levels of the intestine-specific homeobox (ISX), significantly correlate with factors like lesion count, disease stage, and lymph vascular invasion. Tumor cells enhance the secretion of key cytokines such as IL-1β and IL-18, exacerbating disease progression via the ISX-TWIST1 complex. In terms of mechanism, transcriptomic analysis and molecular evidence reveal that ISX interacts with the basic helix-loop-helix (bHLH) domain of TWIST1 through its homeobox domain. This interaction forms a transcriptional complex that activates inflammasomes by directly binding to the conserved sequence "-GGDWYR-" in promoter regions of several NF-κB and inflammasome-related genes (NFKBs, RELs, NLRP1, NLRP3, NEK7, AIM2, and ASC). Elevated levels of IL-18, induced by active inflammasomes, lead to the shift of M0 macrophages into the M2-like phenotype within the hepatic microenvironment. In mice with liver-specific ISX mutations, inflammasome-related genes and activities were eliminated, stopping disease progression in an acute hepatic disease model. These findings underscore the critical role of the ISX-TWIST1 complex in liver disease and tumor progression on both mechanistic and clinical levels. They also offer new insights for potential preventive and therapeutic targets in liver disease. Citation Format: Li-Ting Wang, Shih-Hsien Hsu. Intestine-specific homeobox edits macrophage polarization in the disease microenvironment by activating inflammasome activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5330.