2. Academic Validation
  3. MALT1 protease inhibition restrains glioblastoma progression by reversing tumor-associated macrophage-dependent immunosuppression

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

  • bioRxiv. 2024 Sep 27:2024.09.26.614808. doi: 10.1101/2024.09.26.614808.
Juliana Hofstätter Azambuja 1 2 3,  Saigopalakrishna S Yerneni 1 4,  Lisa M Maurer 2,  Hannah E Crentsil 2 5,  Gabriela N Debom 6,  Linda Klei 2,  Mei Smyers 2,  Chaim T Sneiderman 6,  Kristina E Schwab 7,  Rajesh Acharya 3,  Yijen Lin Wu 7,  Prasanna Ekambaram 2,  Dong Hu 1 8,  Pete J Gough 9,  John Bertin 9,  Ari Melnick 10,  Gary Kohanbash 6,  Riyue Bao 3 11,  Peter C Lucas 1 3 8 12,  Linda M McAllister-Lucas 2 3 13 12
Affiliations

Affiliations

  • 1 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
  • 2 Department of Pediatrics, University of Pittsburgh School of Medicine; Pittsburgh, Pennsylvania.
  • 3 UPMC Hillman Cancer Center; Pittsburgh, Pennsylvania.
  • 4 Department of Chemical Engineering, Carnegie Mellon University; Pittsburgh, Pennsylvania.
  • 5 Medical Scientist Training Program (MSTP), University of Pittsburgh School of Medicine; Pittsburgh, Pennsylvania.
  • 6 Department of Neurological Surgery, University of Pittsburgh School of Medicine; Pittsburgh, Pennsylvania.
  • 7 Rangos Research Center Animal Imaging Core, UPMC Children's Hospital of Pittsburgh; Pittsburgh, Pennsylvania.
  • 8 Department of Pathology, University of Pittsburgh School of Medicine; Pittsburgh, Pennsylvania.
  • 9 Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area, GlaxoSmithKline; King of Prussia, Pennsylvania.
  • 10 Division of Hematology and Oncology, Cornell University, New York, New York.
  • 11 Department of Medicine, University of Pittsburgh; Pittsburgh, Pennsylvania.
  • 12 Mayo Clinic Comprehensive Cancer Center, Rochester, Minnesota.
  • 13 Department of Pediatrics and Adolescent Medicine, Mayo Clinic, Rochester, Minnesota.
PMID: 39386586 DOI: 10.1101/2024.09.26.614808
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-κB 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.

Keywords

MALT1; brain tumor; glioblastoma; macrophage; tumor immune microenvironment.

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