Long-Term MALT1 Inhibition in Adult Mice Without Severe Systemic Autoimmunity

Demeyer, Annelies; Driege, Yasmine; Skordos, Ioannis; Coudenys, Julie; Lemeire, Kelly; Elewaut, Dirk; Staal, Jens; Beyaert, Rudi

doi:10.1016/j.isci.2020.101557

Cited by 14 publications

(11 citation statements)

References 38 publications

(92 reference statements)

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“…Additionally, preclinical safety assessment of an allosteric small molecule inhibitor of MALT1 (MLT-943) in naïve rats and dogs demonstrated Treg loss and progressive lymphadenopathy, lymphocytic infiltration of multiple tissues and gastrointestinal toxicity following prolonged dosing ( 14 ). In contrast, a recent study using conditional inactivation of MALT1 in adult mice did not report systemic inflammation, despite reduced Treg numbers, indicating that the relationship between MALT1 activity, Treg reduction and subsequent systemic inflammation remains uncertain ( 15 ). Similarly, an allosteric small molecule inhibitor of MALT1 was recently described which maintained T-effector cell/Treg homeostasis in vivo ( 16 ).…”

Section: Introductionmentioning

confidence: 96%

Pharmacological Inhibition of MALT1 Ameliorates Autoimmune Pathogenesis and Can Be Uncoupled From Effects on Regulatory T-Cells

Biswas¹,

Chalishazar²,

Helou³

et al. 2022

Front. Immunol.

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MALT1 forms part of a central signaling node downstream of immunoreceptor tyrosine-based activation motif (ITAM)-containing receptors, across a broad range of immune cell subsets, and regulates NF-κB driven transcriptional responses via dual scaffolding-protease activity. Allosteric inhibition of MALT1 activity has demonstrated benefit in animal models of inflammation. However, development of MALT1 inhibitors to treat autoimmune and inflammatory diseases (A&ID) has been hindered by reports linking MALT1 inhibition and genetic loss-of-function to reductions in regulatory T-cell (Treg) numbers and development of auto-inflammatory syndromes. Using an allosteric MALT1 inhibitor, we investigated the consequence of pharmacological inhibition of MALT1 on proinflammatory cells compared to regulatory T-cells. Consistent with its known role in ITAM-driven responses, MALT1 inhibition suppressed proinflammatory cytokine production from activated human T-cells and monocyte-derived macrophages, and attenuated B-cell proliferation. Oral administration of a MALT1 inhibitor reduced disease severity and synovial cytokine production in a rat collagen-induced arthritis model. Interestingly, reduction in splenic Treg numbers was less pronounced in the context of inflammation compared with naïve animals. Additionally, in the context of the disease model, we observed an uncoupling of anti-inflammatory effects of MALT1 inhibition from Treg reduction, with lower systemic concentrations of inhibitor needed to reduce disease severity compared to that required to reduce Treg numbers. MALT1 inhibition did not affect suppressive function of human Tregs in vitro. These data indicate that anti-inflammatory efficacy can be achieved with MALT1 inhibition without impacting the number or function of Tregs, further supporting the potential of MALT1 inhibition in the treatment of autoimmune disease.

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Section: Introductionmentioning

confidence: 96%

Pharmacological Inhibition of MALT1 Ameliorates Autoimmune Pathogenesis and Can Be Uncoupled From Effects on Regulatory T-Cells

Biswas¹,

Chalishazar²,

Helou³

et al. 2022

Front. Immunol.

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“…Small molecule MALT1 inhibitors have already shown promising results in a number of preclinical cancer models for ABC-DLBCL, in which MALT1 is also constitutively activated [ 48 ]. However, several studies, including work from our group, have recently shown that long-term inhibition of MALT1 proteolytic activity is associated with systemic autoimmunity due to defective regulatory T cell function and increased effector T cell function, raising concerns about the safety of MALT1 inhibition [ 49 , 50 , 51 , 52 ]. Therefore, because of its more specific expression in certain epithelial cells, direct targeting of CARD14 (instead of MALT1) may be a more preferred approach in PCa treatment.…”

Section: Discussionmentioning

confidence: 99%

CARD14 Signalling Ensures Cell Survival and Cancer Associated Gene Expression in Prostate Cancer Cells

et al. 2022

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Prostate cancer (PCa) is one of the most common cancer types in men and represents an increasing global problem due to the modern Western lifestyle. The signalling adapter protein CARD14 is specifically expressed in epithelial cells, where it has been shown to mediate NF-κB signalling, but a role for CARD14 in carcinoma has not yet been described. By analysing existing cancer databases, we found that CARD14 overexpression strongly correlates with aggressive PCa in human patients. Moreover, we showed that CARD14 is overexpressed in the LNCaP PCa cell line and that knockdown of CARD14 severely reduces LNCaP cell survival. Similarly, knockdown of BCL10 and MALT1, which are known to form a signalling complex with CARD14, also induced LNCaP cell death. MALT1 is a paracaspase that mediates downstream signalling by acting as a scaffold, as well as a protease. Recent studies have already indicated a role for the scaffold function of MALT1 in PCa cell growth. Here, we also demonstrated constitutive MALT1 proteolytic activity in several PCa cell lines, leading to cleavage of A20 and CYLD. Inhibition of MALT1 protease activity did not affect PCa cell survival nor activation of NF-κB and JNK signalling, but reduced expression of cancer-associated genes, including the cytokine IL-6. Taken together, our results revealed a novel role for CARD14-induced signalling in regulating PCa cell survival and gene expression. The epithelial cell type-specific expression of CARD14 may offer novel opportunities for more specific therapeutic targeting approaches in PCa.

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“…Since the increased IFNγ production during incomplete C11BM inhibition provokes PD-L1 expression in the melanoma cells, the combination of MALT1 inhibitors and anti-PD1 immune checkpoint therapy exhibits synergistic effects in the inhibition of tumor growth [ 105 ]. Whether it is possible to achieve a MALT1 inhibition strong enough to boost the immune response by inhibiting Treg expansion and function, while avoiding severe systemic autoimmunity at the same time, is still under debate [ 106 , 107 ]. Nevertheless, it is tempting to speculate that a short-term application of MALT1 inhibitors in combination with immune checkpoint inhibitors could support the T cell-mediated anti-tumor reaction and thus prove beneficial for cancer patients.…”

Section: Malt1 As a Potential Therapeutic Target In Solid Tumorsmentioning

confidence: 99%

The Paracaspase MALT1 in Cancer

et al. 2022

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Almost twenty years ago, the importance of the paracaspase MALT1 in antigen receptor-induced NF-κB activation was first described. Since then, several other immune receptors, G-protein-coupled receptors, and receptor tyrosine kinases were identified as relying on MALT1 to induce NF-κB activation. In various hematological malignancies and solid tumors, MALT1 is constitutively activated and drives chronic NF-κB target gene expression. Deregulated MALT1 activity in cancer thus promotes tumor cell survival, proliferation, and metastasis. Since the molecular function of MALT1 partially requires its protease activity, pharmacological targeting of MALT1 may represent a promising anti-cancer strategy. Here, we review the molecular features of MALT1 activation and function as well as the therapeutic potential of MALT1 inhibition in hematological malignancies and solid tumors.

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Long-Term MALT1 Inhibition in Adult Mice Without Severe Systemic Autoimmunity

Cited by 14 publications

References 38 publications

Pharmacological Inhibition of MALT1 Ameliorates Autoimmune Pathogenesis and Can Be Uncoupled From Effects on Regulatory T-Cells

Pharmacological Inhibition of MALT1 Ameliorates Autoimmune Pathogenesis and Can Be Uncoupled From Effects on Regulatory T-Cells

CARD14 Signalling Ensures Cell Survival and Cancer Associated Gene Expression in Prostate Cancer Cells

The Paracaspase MALT1 in Cancer

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