Abstract LB323: Deciphering the immunomodulatory role of IL-19 in glioblastoma-promoting ecosystem: Insights into glioblastoma stem cell-tumor-associated macrophage symbiosis

Abstract Glioblastoma multiforme (GBM) stands out as a highly aggressive and resistant brain tumor, characterized by profound immunosuppression and chemoresistance, resulting in a dismal 5% survival rate at the five-year mark. Glioblastoma Stem Cells (GSCs) drive the progression of GBM, orchestrating tumor initiation, growth, and therapeutic resistance. The symbiotic interplay between GSCs and tumor-associated macrophages (TAMs) within hypoxic and perivascular niches is pivotal for sustaining tumorigenesis and immunosuppression. In this study, Interleukin-19 (IL-19), a member of the IL-10 family, was identified among the top five immune-related genes strongly associated with poor survival in patients with GBM from TCGA and Taiwan GBM cohorts. However, the function of IL-19 in glioblastoma is completely unknown. Genomic screening identified IL-19 as a predicted immunosuppressive cytokine in the peritumoral region, associated with poor survival in GBM patients. Blocking IL-19 inhibits both temozolomide (TMZ) -sensitive and TMZ-resistant tumor progression. Molecular studies revealed that IL-19 promotes TMZ-resistant GBM cell migration and invasion through a novel IL-19/β-catenin/WISP1 signaling. Single-cell transcriptome analysis showed that blocking IL-19 promotes T cell activation, upregulates the effector function of T cell subsets, and reprograms TAM subsets toward weakened pro-tumoral phenotypes with lower Arginase 1 expression. Silencing IL-19 significantly disrupts self-renewal GSC activity through a novel IL-19/S100A4/WISP1 signaling. Additionally, we identified that TAM-derived IL-19 positively regulates GSC self-renewal through the paracrine IL-19/WISP1 axis. Our study demonstrates IL-19 as a linchpin in the complex GSC-TAM symbiosis, leading to GSC maintenance and immunosuppression, providing critical insights into the immune landscape orchestrated by GSC-TAM symbiosis Citation Format: Gilbert Aaron Lee, Cheng-Yu Chen. Deciphering the immunomodulatory role of IL-19 in glioblastoma-promoting ecosystem: Insights into glioblastoma stem cell-tumor-associated macrophage symbiosis abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (7Suppl): Abstract nr LB323.