Pharmacological Inhibition of MALT1 Protease Leads to a Progressive IPEX-Like Pathology

Martin, Kea; Junker, Ursula; Tritto, Elaine; Sutter, Esther; Rubic-Schneider, Tina; Morgan, Hannah L.; Niwa, Satoru; Li, Jianping; Schlapbach, Achim; Walker, Dana; Bigaud, Marc; Berthou, Christian; Littlewood‐Evans, Amanda; Rudolph, Bettina; Laisney, Marc; David, Lior; Beltz, Karen; Quancard, Jean; Bornancin, Frédéric; Ribrioux, Natasa Zamurovic; Calzascia, Thomas

doi:10.3389/fimmu.2020.00745

Cited by 28 publications

(37 citation statements)

References 44 publications

(109 reference statements)

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“…Since the PD1/PD-L1 axis was already shown to contribute to T cells dysregulations in both human and mouse models of CLL, we used MI-2 therapy as a pretreatment for checkpoint blockade with anti-PD-L1 antibody in immunocompetent TCL1-leukemia bearing mice ( 6 , 29 ). Considering that long-term inhibition of Tregs functions can lead to autoimmune pathology ( 30 ), MI-2 inhibitor was used only before anti-PD-L1 therapy ( Figure 6A ). The anti-PD-L1 therapy did not affect the percentage of T cells already elevated by MI-2 ( Figure 6B ).…”

Section: Resultsmentioning

confidence: 99%

A Specific CD44lo CD25lo Subpopulation of Regulatory T Cells Inhibits Anti-Leukemic Immune Response and Promotes the Progression in a Mouse Model of Chronic Lymphocytic Leukemia

et al. 2022

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Regulatory T cells (Tregs) are capable of inhibiting the proliferation, activation and function of T cells and play an important role in impeding the immune response to cancer. In chronic lymphocytic leukemia (CLL) a dysfunctional immune response and elevated percentage of effector-like phenotype Tregs have been described. In this study, using the Eµ-TCL1 mouse model of CLL, we evaluated the changes in the Tregs phenotype and their expansion at different stages of leukemia progression. Importantly, we show that Tregs depletion in DEREG mice triggered the expansion of new anti-leukemic cytotoxic T cell clones leading to leukemia eradication. In TCL1 leukemia-bearing mice we identified and characterized a specific Tregs subpopulation, the phenotype of which suggests its role in the formation of an immunosuppressive microenvironment, supportive for leukemia survival and proliferation. This observation was also confirmed by the gene expression profile analysis of these TCL1-specific Tregs. The obtained data on Tregs are consistent with those described so far, however, above all show that the changes in the Tregs phenotype described in CLL result from the formation of a specific, described in this study Tregs subpopulation. In addition, functional tests revealed the ability of Tregs to inhibit T cells that recognize model antigens expressed by leukemic cells. Moreover, inhibition of Tregs with a MALT1 inhibitor provided a therapeutic benefit, both as monotherapy and also when combined with an immune checkpoint inhibitor. Altogether, activation of Tregs appears to be crucial for CLL progression.

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Section: Resultsmentioning

confidence: 99%

A Specific CD44lo CD25lo Subpopulation of Regulatory T Cells Inhibits Anti-Leukemic Immune Response and Promotes the Progression in a Mouse Model of Chronic Lymphocytic Leukemia

et al. 2022

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“…Besides mepazine, potent selective Malt1 paracaspase pharmacologic inhibitors have been described that may also be suited in the setting of solid organ transplantation ( 44 , 49 – 51 ). The efficacy/safety profile of these compounds need to be tested in our experimental model, in particular regarding the effect of prolonged use on the pool of effector and regulatory immune cell subsets.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, unless tolerance to alloantigens can be induced, life-long immunosuppressive therapy is required after SOT. In this regard, a recent preclinical study has revealed potential safety issues regarding prolonged in vivo Malt1 protease inhibition, in particular regarding the deleterious effect on peripheral Treg ( 51 ). In the study, the authors show that as opposed to mepazine, the chronic administration of a novel potent inhibitor induced a dose-dependent reduction in Treg with associated autoimmunity, reminiscent of the Malt-ki mice.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Potential of Targeting Malt1-Dependent TCR Downstream Signaling to Promote the Survival of MHC-Mismatched Allografts

et al. 2020

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Strategies targeting T cells are the cornerstone of immunosuppression after solid organ transplantation. The transcription factor NF-κB is a key regulator of downstream T-cell activation and induction of inflammatory mediators; its full activation via antigen receptor engagement requires both the scaffold and the protease activity of the paracaspase Malt1. Experimental studies have highlighted that Malt1-deficient mice were resistant to experimental autoimmune encephalomyelitis, although they lacked peripheral regulatory T cells (Treg). Here, we compared targeting Malt1 versus using calcineurin inhibitors as immunosuppression in a stringent experimental transplantation model. We found that Malt1-deficiency impaired Th1-mediated alloresponses in vitro and in vivo and significantly prolonged MHC-mismatched skin allograft survival, compared to cyclosporine. However, it paradoxically enhanced Th17 differentiation in the transplantation setting. Interestingly, more selective inhibition of Malt1 protease activity in wild-type mouse and human peripheral T cells in vitro led to attenuation of alloreactive Th1 cells, while preserving preexisting Treg in the peripheral T-cell pool, and without promoting Th17 differentiation. Thus, there is a place for further investigation of the role of Malt1 signaling in the setting of transplantation.

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“…Lack of lethal autoimmunity in our Malt1-i-PD mice could still be due to the incomplete inactivation of MALT1. However, partial MALT1 inactivation in our mice mimics pharmacological targeting (Martin et al, 2020a). Conceptually our model is therefore very relevant in the context of therapeutic targeting of MALT1 with small compound inhibitors.…”

Section: Limitations Of the Studymentioning

confidence: 93%

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

et al. 2020

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Summary The protease MALT1 is a key regulator of NF-κB signaling and a novel therapeutic target in autoimmunity and cancer. Initial enthusiasm supported by preclinical results with MALT1 inhibitors was tempered by studies showing that germline MALT1 protease inactivation in mice results in reduced regulatory T cells and lethal multi-organ inflammation due to expansion of IFN-γ-producing T cells. However, we show that long-term MALT1 inactivation, starting in adulthood, is not associated with severe systemic inflammation, despite reduced regulatory T cells. In contrast, IL-2-, TNF-, and IFN-γ-producing CD4 + T cells were strongly reduced. Limited formation of tertiary lymphoid structures was detectable in lungs and stomach, which did not affect overall health. Our data illustrate that MALT1 inhibition in prenatal or adult life has a different outcome and that long-term MALT1 inhibition in adulthood is not associated with severe side effects.

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Pharmacological Inhibition of MALT1 Protease Leads to a Progressive IPEX-Like Pathology

Cited by 28 publications

References 44 publications

A Specific CD44lo CD25lo Subpopulation of Regulatory T Cells Inhibits Anti-Leukemic Immune Response and Promotes the Progression in a Mouse Model of Chronic Lymphocytic Leukemia

A Specific CD44lo CD25lo Subpopulation of Regulatory T Cells Inhibits Anti-Leukemic Immune Response and Promotes the Progression in a Mouse Model of Chronic Lymphocytic Leukemia

Therapeutic Potential of Targeting Malt1-Dependent TCR Downstream Signaling to Promote the Survival of MHC-Mismatched Allografts

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

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