Role of MALT1 in regulating the breast cancer immune microenvironment

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PROJECT SUMMARY: Triple-negative breast cancer (TNBC) represents ~15% of invasive breast cancer cases, with disproportionately high prevalence in African-American and Hispanic women, and is defined by the lack of expression of estrogen receptor, progesterone receptor, and HER2 (ER-/PR-/HER2-). Due to the absence of currently targetable molecular drivers, treatment for TNBC still relies on non-specific toxic chemotherapeutics and outcomes remain poor. As a result, there is a pressing need to develop molecularly-informed, targeted therapies to treat TNBC. In this proposal, we investigate MALT1 protease as a potential new therapeutic target in a subset of TNBC. MALT1 is the enzymatic effector protein of a signaling complex composed of proteins CARMA3, BCL10 and MALT1 (CBM signalosome) that functions downstream of specific G protein-coupled receptors (GPCRs) to drive oncogenic reprogramming in a subset of carcinomas including TNBC. GPCRs known to activate MALT1 in breast cancer include PAR1, AGTR1, and the LPARs (LPAR1-3) and overexpression of these GPCRs is associated with aggressive breast cancer behavior in experimental models and worse clinical outcomes for human patients. We recently found that the GPCR/MALT1 signaling axis drives a program of epithelial-to-mesenchymal transition (EMT) in TNBC. Since tumor cells undergoing EMT are known to promote a permissive, immune- suppressed microenvironment, we propose to investigate the role of the GPCR/MALT1 signaling axis in the regulation of the tumor immune microenvironment. Our preliminary data indicate that MALT1 is a key mediator of immune suppression induced by GPCR+ TNBC, suggesting that inhibiting MALT1 protease activity in TNBC cells may have a beneficial effect. Additionally, inhibition of MALT1 protease activity in immune cells has recently been found to preferentially impair Treg function, tipping the balance between regulatory and effector T cells to promote heightened immunoreactivity. Together, these observations in TNBC cells and immune cells lead us to hypothesize that pharmaceutic MALT1 inhibition may have dual therapeutic benefit in GPCR+ TNBC by (1) preventing MALT1-mediated tumor immune suppression from within cancer cells and (2) altering the composition of tumor infiltrating immune cells in favor of anti-tumor immunity. This proposal will evaluate this hypothesis via a combination of elegant in vitro and in vivo model systems. The overarching goal of our proposal is to rigorously evaluate the role of MALT1 as a pathogenic driver of TNBC and to test pharmaceutic MALT1 inhibition as a novel therapeutic strategy in this difficult-to-treat disease.