Nuclear defective il-33 drives an anti-tumorigenic microenvironment in glioblastoma

Abstract Despite a sophisticated treatment regimen, including surgery, chemotherapy, and radiotherapy, survival outcomes for glioblastoma remain at a dismal 14.6 months. Multi-omics profiling have established that myeloid phagocytes drive glioma progression and contribute to therapeutic resistance. However, effective targeting of this axis remains an unmet clinical opportunity. Previously, we found that the dual-function (secreted and nuclear) cytokine IL-33 is a key regulator of the inflammatory microenvironment that aids glioma tumorigenesis through phenotypic and functional changes in the innate immune cell repertoire. Strikingly, when IL-33 is prevented from entering the nucleus, by deletion of its nuclear localization signal (ΔNLS IL-33), but is still secreted, in vivo tumor growth is dramatically suppressed resulting in extended long-term survival. Using spatial transcriptomics and multiplex immunohistochemistry with temporal resolution at different stages of tumor progression, we identified a population of glioma-inhibitory macrophages (GIMs) unique to this suppressive environment. Assessment of xenografts generated from patient brain tumor initiating cells found an enrichment of GIMs in xenografts with long-term survival (>300 days) compared to short-term survivors (<100 days). The ability of GIMs to inhibit glioma progression was further highlighted when tumors established using a combination of ΔNLS IL-33 expressing cancer cells together with highly tumorigenic cells resulted in a growth inhibitory environment that significantly prolonged survival through the polarization and activation of GIMs. Additional characterization of this phenotype and development of clinical strategies to deliver ΔNLS IL-33 to brain tumors is warranted to determine if recruitment and activation of GIMs is a translatable therapeutic strategy for glioma patients.