MALT1 protease inhibition restrains glioblastoma progression by reversing tumor-associated macrophage-dependent immunosuppression

Hofstatter Azambuja, J.; Yerneni, S. S.; Maurer, L. M.; Crentsil, H. E.; Debom, G. N.; Klei, L.; Smyers, M.; Sneiderman, C. T.; Schwab, K. E.; Acharya, R.; Lin Wu, Y.; Ekambaram, P.; Hu, D.; Gough, P. J.; Bertin, J.; Melnick, A.; Kohanbash, G.; Bao, R.; Lucas, P. C.; McAllister-Lucas, L. M.

doi:10.1101/2024.09.26.614808

Home/Archive/bioRxiv

bioRxiv · 10.1101/2024.09.26.614808

MALT1 protease inhibition restrains glioblastoma progression by reversing tumor-associated macrophage-dependent immunosuppression

View original source ↗Export metadata ↓

Abstract

MALT1 protease is an intracellular signaling molecule that promotes tumor progression via cancer cell-intrinsic and cancer cell-extrinsic mechanisms. MALT1 has been mostly studied in lymphocytes, and little is known about its role in tumor-associated macrophages. Here, we show that MALT1 plays a key role in glioblastoma (GBM)-associated macrophages. Mechanistically, GBM tumor cells induce a MALT1-NF-{kappa}B signaling axis within macrophages, leading to macrophage migration and polarization toward an immunosuppressive phenotype. Inactivation of MALT1 protease promotes transcriptional reprogramming that reduces migration and restores a macrophage "M1-like" phenotype. Preclinical in vivo analysis shows that MALT1 inhibitor treatment results in increased immuno-reactivity of GBM-associated macrophages and reduced GBM tumor growth. Further, the addition of MALT1 inhibitor to temozolomide reduces immunosuppression in the tumor microenvironment, which may enhance the efficacy of this standard-of-care chemotherapeutic. Together, our findings suggest that MALT1 protease inhibition represents a promising macrophage-targeted immunotherapeutic strategy for the treatment of GBM. Graphical abstract. O_FIG O_LINKSMALLFIG WIDTH=196 HEIGHT=200 SRC="FIGDIR/small/614808v1_ufig1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@18c969eorg.highwire.dtl.DTLVardef@f48f0dorg.highwire.dtl.DTLVardef@1dbbbb1org.highwire.dtl.DTLVardef@ff8237_HPS_FORMAT_FIGEXP M_FIG The effects of tumor cell-induced CARD9-BCL10-MALT1 (CBM) activation (left) and MALT1 protease inhibition (right) on GBM associated macrophages in the tumor microenvironment. Cartoon of cellular components of a GBM tumor with an immunosuppressive TME characterized by "M2-like macrophages" (left) and conversion to a more immune-reactive tumor microenvironment characterized by "M1-like macrophages and increased effector T-cells (right) as a result of MALT1 protease inhibition. C_FIG

Explore related subjects

cancer biology Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Hofstatter Azambuja, J., Yerneni, S. S., Maurer, L. M., Crentsil, H. E., Debom, G. N., Klei, L., Smyers, M., Sneiderman, C. T., Schwab, K. E., Acharya, R., Lin Wu, Y., Ekambaram, P., Hu, D., Gough, P. J., Bertin, J., Melnick, A., Kohanbash, G., Bao, R., Lucas, P. C., McAllister-Lucas, L. M.. 2024-09-27. MALT1 protease inhibition restrains glioblastoma progression by reversing tumor-associated macrophage-dependent immunosuppression. https://doi.org/10.1101/2024.09.26.614808

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Regulation of the Epstein-Barr Epigenome by Histone Variant MacroH2A

Histone variants play an important role in regulating chromatin dynamics of Epstein-Barr Virus (EBV). Here, we investigate the role of histone variant macroH2A in EBV chromatin structure, gene expression and copy number control during latent infection. ChIP-seq analysis in EBV+ SNU719 gastric carcinoma and Mutu I Burkitt lymphoma cells revealed that macroH2A was most enriched at repetitive DNA elements, including oriLyt, BHLF1, LF3 and terminal repeat (TR) regions of the EBV genome. MacroH2A depletion in EBV-associated gastric cancer cell line SNU719 led to a small increase in some viral lytic genes and increase in viral DNA copy number. RNAseq transcriptomics after macroH2A depletion identified major perturbations in cellular gene pathways, including beta-catenin/TCF signaling and chromatin remodeling. Depletion of macroH2A during EBV lytic reactivation reduced EBV lytic gene activation, but increased EBV DNA copy number. Previous study demonstrated a colocalization and cooperative binding between histone variant H2A.Z and EBNA1. We now show that depletion of macroH2A causes an increase in both H2A.Z and EBNA1 at oriP and cellular binding sites for EBNA1. We also found that gammaH2AX localizes to oriP and that this depends on macroH2A. Finally, we show that CRISPR/Cas9 knockout of macroH2A increases the replication and episome maintenance of oriP-containing plasmids. Taken together, these findings indicate that macroH2A localizes to the repetitive elements of EBV, including oriLyt, and can function to limit H2A.Z and EBNA1 binding at oriP, which alters DNA damage signaling at oriP and limits episomal replication. These findings provide a novel role for macroH2A in maintaining EBV copy number and genome integrity.

cancer biology↗

bioRxiv2026

Epigenomic circuits shaping cellular heterogeneity in pleural mesothelioma

Pleural mesothelioma (PM) is an aggressive and lethal malignancy with current treatments offering limited clinical benefit. In this study, we utilized single-cell chromatin accessibility and transcriptomic profiling of patient-matched samples to infer the epigenomic regulation underlying cellular heterogeneity in PM. High-resolution epigenomic profiling suggested transcriptional regulators with putative pro-tumoral roles in mesothelioma, whose function was experimentally tested using genetic perturbations across four PM cell lines. Furthermore, we observed several putative associations between epigenomic circuits and macrophage ontogeny, a sarcomatoid-like neoplastic state, and a fetal-like endothelial cell state. Our analysis also showed similarities between the chromatin accessibility landscapes of exhausted CD8 T and KLRC1 natural killer cells and identified NR4A2 as a potential shared regulator of dysfunction in both lymphocyte subsets. We further identified a state-specific distal enhancer near NR4A2 and experimentally validated its regulation of NR4A2 expression in Jurkat cells. Together, we provide an epigenomic map of PM and nominate candidate transcription factors and regulatory elements for future functional investigation, including their potential relevance to epigenetic editing strategies to limit tumor growth and enhance anti-tumor immunity.

cancer biology↗

bioRxiv2026

Multimodal Liquid Biopsy Improves Longitudinal Circulating Tumor DNA Detection in Children with Central Nervous System Tumors

Background: Circulating tumor DNA (ctDNA) is a promising biomarker for pediatric central nervous system (CNS) tumors, but limitations in sensitivity and universally accepted detection criteria remain. We evaluated multimodal ctDNA detection using a novel composite scoring framework integrating mutation, copy number, and fragmentomic analysis in longitudinal plasma and CSF samples from children with CNS tumors. Methods: Tumor, blood and/or CSF samples were collected from pediatric CNS tumor patients. DNA was extracted from plasma, CSF, tumor, and whole blood. All samples underwent targeted and whole genome sequencing. Plasma and CSF samples were evaluated for ctDNA positivity--defined by a composite score [≥]2--utilizing a tri-modal approach of whole genome sequencing for copy number alterations and fragmentomics and targeted sequencing. Results: The cohort included 28 patients: medulloblastoma (39%), diffuse midline glioma (25%), high-grade glioma (18%), pilocytic astrocytoma (11%), and ependymoma (7%). A total of 140 plasma and 27 CSF samples were collected longitudinally. Combining all three modalities identified ctDNA in 70% of CSF and 17% of plasma samples, exceeding rates achieved by any single modality alone. Post-diagnosis plasma ctDNA positivity was significantly associated with worse progression-free and overall survival. CSF demonstrated significantly higher ctDNA signal intensity than plasma across all assay modalities. Conclusions: A multimodal composite scoring approach improves longitudinal ctDNA detection in pediatric CNS tumors. Although CSF remains the most sensitive biofluid, plasma ctDNA reflects disease progression in select patients. These findings support integrated, multimodal liquid biopsy strategies for disease monitoring and highlight the need for prospective validation of standardized detection criteria.

cancer biology↗