Role of MALT1 in regulating the breast cancer immune microenvironment

项目总结： 三阴性乳腺癌(TNBC)约占浸润性乳腺癌病例的15%， 在非裔美国人和西班牙裔妇女中发病率很高，其定义是缺乏雌激素的表达 受体、孕激素受体和HER2(ER-/PR-/HER2-)。由于缺乏目前可瞄准的 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，结果仍然存在 可怜。因此，迫切需要开发分子知情的靶向疗法来治疗TNBC。 在这项建议中，我们研究了MALT1蛋白水解酶作为一种潜在的新的治疗靶点的TNBC的子集。 MALT1是由CARMA3、BCL10和CARMA3组成的信号复合体的酶效应蛋白。 MALT1(CBM信号体)，作用于特定的G蛋白偶联受体(GPCRs)下游，以驱动 包括TNBC在内的一组癌症中的致癌重编程。GPCRs可激活乳房中的MALT1 癌症包括PAR1、AGTR1和LPAR(LPAR1-3)，这些GPCRs的过度表达与 在实验模型中有侵袭性的乳腺癌行为，对人类患者的临床结果更差。 我们最近发现，GPCR/MALT1信号轴驱动上皮细胞到间充质细胞的程序 TNBC中的过渡(EMT)。由于已知接受EMT的肿瘤细胞可以促进一种允许的、免疫的- 受抑制的微环境，我们建议研究GPCR/MALT1信号轴在 调节肿瘤免疫微环境。我们的初步数据表明，MALT1是一个关键的调节因子 GPCR+TNBC诱导的免疫抑制，提示抑制TNBC中MALT1蛋白的活性 细胞可能会有有益的效果。此外，最近对免疫细胞中MALT1蛋白酶活性的抑制 已发现优先损害Treg功能，使调节性和效应性T细胞之间的平衡倾向于 促进免疫反应增强。总之，在TNBC细胞和免疫细胞中的这些观察结果引导我们 假设药物抑制MALT1在GPCR+TNBC中可能具有双重治疗益处，通过(1) 从癌细胞内阻止MALT1介导的肿瘤免疫抑制和(2)改变成分 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对这一假设进行评估 一个优雅的体外和活体模型系统的结合。我们提案的首要目标是严格执行 评估MALT1作为TNBC致病驱动因素的作用，并测试药物对MALT1的抑制作用 在这一难以治疗的疾病中的新治疗策略。

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.