Role of MALT1 in regulating the breast cancer immune microenvironment

项目概要： 三阴性乳腺癌（TNBC）占浸润性乳腺癌病例的约15%， 在非洲裔美国人和西班牙裔妇女中的高患病率，并通过缺乏雌激素表达来定义 受体、孕酮受体和HER 2（ER-/PR-/HER 2-）。由于缺乏目前的目标， 分子驱动因素，TNBC的治疗仍然依赖于非特异性毒性化疗药物， 扶贫因此，迫切需要开发分子信息的靶向疗法来治疗TNBC。 在这个提议中，我们研究了MALT 1蛋白酶作为TNBC亚组中潜在的新治疗靶点。 MALT 1是信号传导复合物的酶效应蛋白，该信号传导复合物由蛋白质CARMA 3、BCL 10和 MALT 1（CBM信号体），在特异性G蛋白偶联受体（GPCR）下游发挥作用， 包括TNBC在内的癌症亚群中的致癌重编程。已知激活乳腺中MALT 1的GPCR 癌症包括PAR 1、AGTR 1和LPAR（LPAR 1 -3），这些GPCR的过表达与 在实验模型中具有侵袭性乳腺癌行为，对人类患者的临床结果更差。 我们最近发现，GPCR/MALT 1信号轴驱动上皮细胞向间质细胞转化的程序， TNBC中的EMT。由于经历EMT的肿瘤细胞已知会促进一种允许的免疫- 抑制的微环境，我们建议研究GPCR/MALT 1信号轴在细胞凋亡中的作用。 调节肿瘤免疫微环境。我们的初步数据表明，MALT 1是一个关键的调解人， GPCR+ TNBC诱导的免疫抑制，表明抑制TNBC中的MALT 1蛋白酶活性 细胞可能具有有益的效果。此外，最近，免疫细胞中MALT 1蛋白酶活性的抑制已被发现。 发现它优先损害Treg功能，使调节性T细胞和效应性T细胞之间的平衡倾斜， 提高免疫反应性。总之，这些对TNBC细胞和免疫细胞的观察使我们得出 假设药物MALT 1抑制可在GPCR+ TNBC中具有双重治疗益处， 防止癌细胞内MALT 1介导的肿瘤免疫抑制和（2）改变组合物 肿瘤浸润性免疫细胞有利于抗肿瘤免疫。本提案将通过以下方式评估这一假设： 优雅的体外和体内模型系统的组合。我们提案的首要目标是严格 评估MALT 1作为TNBC的致病驱动因素的作用，并测试药物MALT 1抑制作为TNBC的致病驱动因素。 新的治疗策略，在这种难以治疗的疾病。

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.