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O'Neill, T.J. ; Tofaute, M.J. ; Krappmann, D.

Function and targeting of MALT1 paracaspase in cancer.

Cancer Treat. Rev. 117:102568 (2023)
Verlagsversion DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
The paracaspase MALT1 has emerged as a key regulator of immune signaling, which also promotes tumor development by both cancer cell-intrinsic and -extrinsic mechanisms. As an integral subunit of the CARD11-BCL10-MALT1 (CBM) signaling complex, MALT1 has an intriguing dual function in lymphocytes. MALT1 acts as a scaffolding protein to drive activation of NF-κB transcription factors and as a protease to modulate signaling and immune activation by cleavage of distinct substrates. Aberrant MALT1 activity is critical for NF-κB-dependent survival and proliferation of malignant cancer cells, which is fostered by paracaspase-catalyzed inactivation of negative regulators of the canonical NF-κB pathway like A20, CYLD and RelB. Specifically, B cell receptor-addicted lymphomas rely strongly on this cancer cell-intrinsic MALT1 protease function, but also survival, proliferation and metastasis of certain solid cancers is sensitive to MALT1 inhibition. Beyond this, MALT1 protease exercises a cancer cell-extrinsic role by maintaining the immune-suppressive function of regulatory T (Treg) cells in the tumor microenvironment (TME). MALT1 inhibition is able to convert immune-suppressive to pro-inflammatory Treg cells in the TME of solid cancers, thereby eliciting a robust anti-tumor immunity that can augment the effects of checkpoint inhibitors. Therefore, the cancer cell-intrinsic and -extrinsic tumor promoting MALT1 protease functions offer unique therapeutic opportunities, which has motivated the development of potent and selective MALT1 inhibitors currently under pre-clinical and clinical evaluation.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Review
Korrespondenzautor
Schlagwörter Anti-tumor Immunity ; Cbm Complex ; Cancer Therapy ; Lymphoma ; Malt1 ; Precision Medicine; Nf-kappa-b; T-cell; Protease Activity; Ubiquitin Ligase; Activation; Lymphoma; Inhibitors; Ibrutinib; Cleavage; Phosphorylation
ISSN (print) / ISBN 0305-7372
e-ISSN 1532-1967
Zeitschrift Cancer Treatment Reviews
Quellenangaben Band: 117, Heft: , Seiten: , Artikelnummer: 102568 Supplement: ,
Verlag Elsevier
Verlagsort The Boulevard, Langford Lane, Kidlington, Oxford Ox5 1gb, Oxon, England
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Research Unit Signaling and Translation (SAT)
Förderungen Deutsche Forschungsgemeinschaft