YBX1&YBX3 as novel targets to potentiate immune checkpoint blockade response in gliomas.
Ali H, Zhou N, Chen L, van Hijfte L, Tulaiha R, Karri V, Zhou Y, Habashy K, Arrieta VA, Kim KS, Duffy J, Yeeravalli R, Tiek DM, Song X, Mishra S, Horbinski C, Lee-Chang C, Ahmed A, Wang L, Heiland DH, Sonabend AM, Dmello C (2025)
Publication Type: Journal article
Publication year: 2025
Journal
Book Volume: 28
Pages Range: 159-174
Journal Issue: 1
Abstract
BACKGROUND: Glioblastoma (GBM) exhibits profound resistance to CD8⁺ T cell-mediated killing, yet the tumor-intrinsic mechanisms driving this immune evasion remain poorly defined. Our earlier study revealed Checkpoint Kinase 2 (Chek2) as the driver of CD8+ T cell resistance. This study investigates the immunomodulatory program exerted by the CHK2-YBX1&YBX3 regulatory hub. METHODS: Protein-protein interactions were investigated through immunoprecipitation (IP) followed by mass spectrometry (MS) and phosphoproteomics. Single gene knockout of CHEK2, Y-box-binding protein 1 (YBX1), and Y-box-binding protein 3 (YBX3) were generated in human and mouse glioma cells. Transcriptomic and epigenetic alterations were characterized by bulk RNA sequencing and chromatin immunoprecipitation sequencing (ChIP-seq). Single-cell RNA sequencing and spatial transcriptomics analysis were performed to evaluate CHK2-YBX1&YBX3 related phenotype in human GBM tumors. In vivo survival studies were conducted to assess the therapeutic potential of CHK2-YBX1&YBX3 degradation and immune checkpoint blockade (ICB). RESULTS: CHK2, YBX1, and YBX3 exhibited reciprocal positive regulation and depletion of any of these genes resulted in derepression of pro-inflammatory gene expression. Pharmacological inhibition with the drug targeting YBX1 led to degradation of the CHK2-YBX1&YBX3 hub accompanied by enhanced antigen presentation and antigen-specific CD8⁺ T cell proliferation. Combination therapy targeting CHK2-YBX1&YBX3 hub and ICB significantly improved survival in preclinical glioma models. CONCLUSIONS: These findings define a novel glioma-intrinsic immunosuppressive program and proposes targeting the CHK2-YBX1&YBX3 hub to potentiate response to ICB in glioma.
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APA:
Ali, H., Zhou, N., Chen, L., van Hijfte, L., Tulaiha, R., Karri, V.,... Dmello, C. (2025). YBX1&YBX3 as novel targets to potentiate immune checkpoint blockade response in gliomas. Neuro-Oncology, 28(1), 159-174. https://doi.org/10.1093/neuonc/noaf227
MLA:
Ali, Heba, et al. "YBX1&YBX3 as novel targets to potentiate immune checkpoint blockade response in gliomas." Neuro-Oncology 28.1 (2025): 159-174.
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