Abstract 5264: Harnessing glioma-inhibitory macrophages for sustained control of glioblastoma progression

Abstract Despite intensive basic and clinical research over the past 30 years, there has been minimal improvement in outcomes for patients with glioblastoma, the deadliest form of adult brain cancer. Several factors contribute to this therapeutic challenge, including a complex interaction between the tumor and the innate immune compartment of the brain microenvironment, that is thought to support glioma proliferation and treatment resistance. Previously, we established that glioma cells can communicate with microglia/macrophage by producing the dual-function (secreted and nuclear) cytokine interleukin 33 (IL33). We found that IL33 supports the recruitment and reprogramming of pro-tumorigenic macrophage to fuel rapid and fatal tumor growth. However, in contrast, when IL33 is prevented from entering the nucleus, by loss of its nuclear localization signal (ND-IL33), tumor growth is dramatically suppressed. Using multiplex immunohistochemistry across different stages of tumor progression, we uncovered a population of macrophages unique to this growth restrictive environment, which we term glioma-inhibitory macrophages (GIMs). To resolve the molecular features of GIMs, we performed spatial transcriptomics and a computational workflow based on unsupervised deconvolution to identify cell types and activities enriched within the ND-IL33 environment. This strategy revealed that GIMs upregulate phagocytosis and antigen processing/presentation pathways and exhibit features of granulocytic cells. When examining xenografts established from patient-derived brain tumor-initiating cells, we observed a notable increase in the presence of GIMs in xenografts that exhibited long-term survival (>300 days) compared to those with short-term survival (<100 days). The tumor-suppressive nature of GIMs was further supported by experiments in which tumors formed by a combination of ND-IL33-expressing cancer cells and highly tumorigenic cells led to a growth-restrictive environment that significantly extended survival. Further functional characterization of this macrophage phenotype and development of strategies to deliver ND-IL33 to brain tumors is necessary to determine whether the recruitment and activation of GIMs could be an effective therapeutic approach for patients with glioblastoma. Citation Format: Shyam V. Menon, Xueqing Lun, Tala-Maria Mouannes, Peipei Zeng, Varsha T. Manoharan, Jianbo Zhang, Isabelle Carrier, Eduardo Diez, Alisha Poole, Ngoc Ha Dang, Bo Young Ahn, Katalin Osz, Sorana A. Morrissy, Jennifer A. Chan, Daniela F. Quail, Stephen M. Robbins, Donna L. Senger. Harnessing glioma-inhibitory macrophages for sustained control of glioblastoma progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5264.