Abstract 4989: Targeting IL-1β mitigates radiation induced MDSC expansion & improves survival in glioblastoma

Abstract

Abstract Background: Our previous research demonstrated that radiation therapy (RT) for glioblastoma (GBM) induces aberrant myelopoiesis, increasing production of myeloid derived suppressor cells (MDSCs) and exacerbating T-cell suppression. However, the precise biological mechanisms underlying this phenomenon remain unclear. This study aims to elucidate the role of the pro-inflammatory cytokine interleukin-1beta (IL-1β) in RT-induced myelopoiesis and its correlation with poor prognosis in GBM patients. Methods: We conducted an extensive analysis of circulatory immune cells and pro-inflammatory cytokines in GBM patients treated with chemoradiotherapy. Using an orthotopic mouse model of GBM, we investigated the impact of IL-1β on myelopoiesis and survival. Functional assays were employed to examine MDSC expansion. Multi-color flow cytometry was used for immune profiling. Results: We found that RT elevated the plasma IL-1β concentration in both GBM patients and GBM-bearing mice, which also corresponded with an increase of MDSC in blood. In the murine GBM model, RT appeared to promote hematopoietic stem (HSPC) differentiation towards myelopoiesis. This led to increased MDSC precursor cells in the bone marrow, elevated circulating MDSCs in blood, and more infiltration of MDSCs in the tumor microenvironment (TME). Similar effects were observed in GBM-bearing mice following the administration of exogenous IL-1β. In contrast, inhibition of IL-1β using anti-IL-1β antibody during RT led to reduced myelopoiesis. When anti-IL-1β antibody was combined with functional inhibition of MDSCs using phosphodiesterase-5 inhibitor-tadalafil during RT, we observed decreased MDSC infiltration and increased CD8+ T cell infiltration in the TME. The combination approach also extended the survival of GBM-bearing mice after RT longer than either drug alone. Conclusions: Irradiation of GBM appears to induce IL-1β to promote aberrant myelopoiesis and MDSC expansion. A multi-pronged approach to inhibit MDSC production using IL-1β inhibitor and MDSC function using tadalafil during RT may be a promising approach to overcome the immune-suppressive TME of GBM. Citation Format: Subhajit Ghosh, Jiayi Huang, David DeNardo, Dennis Hallahan, Jerry Jaboin, Dinesh Thotala. Targeting IL-1β mitigates radiation induced MDSC expansion & improves survival in glioblastoma [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 4989.