Role of MALT1 in regulating the breast cancer immune microenvironment

MALT1在调节乳腺癌免疫微环境中的作用

• 批准号: 10656975
• 负责人: PETER C LUCAS
• 金额: $ 52.67万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10656975
• 关键词: African American; Antigen Receptors; Antitumor Response; Archives; BCL10 gene; Behavior; Biological Models; Biological Response Modifiers; Biology; Breast Cancer Cell; Breast Cancer Model; CD8-Positive T-Lymphocytes; Carcinoma; Caucasians; Cell Compartmentation; Cells; Clinical; Complex; Data; Disease; ERBB2 gene; Equilibrium; Estrogen Receptors; Experimental Models; F2R gene; G-Protein-Coupled Receptors; Goals; High Prevalence; Hispanic; Human; Immune; Immune Evasion; Immune response; Immunosuppression; Impairment; In Vitro; Knowledge; Link; MAPK8 gene; Malignant Neoplasms; Mediating; Mediator; Molecular; Mucosa- associated lymphoid tissue lymphoma translocation protein-1; Mus; Natural Killer Cells; Oncogenic; Oncology; Outcome; Paracrine Communication; Pathogenicity; Patient-Focused Outcomes; Patients; Peptide Hydrolases; Pharmacy (field); Phenotype; Progesterone Receptors; Proteins; Regulation; Regulatory T-Lymphocyte; Role; Signal Transduction; Signaling Molecule; Specimen; T-Lymphocyte; Testing; Therapeutic; Tumor Immunity; Tumor-infiltrating immune cells; Woman; Work; aggressive breast cancer; anti-tumor immune response; cancer cell; cancer subtypes; cell type; combat; cytokine; effector T cell; epithelial to mesenchymal transition; experience; genetic approach; human model; immunoreactivity; in vivo Model; malignant breast neoplasm; mouse model; neoplastic cell; new therapeutic target; novel therapeutic intervention; overexpression; patient derived xenograft model; permissiveness; pharmacologic; prevent; programmed cell death ligand 1; programs; rational design; recruit; response; sample collection; targeted treatment; therapy resistant; triple-negative invasive breast carcinoma; tumor; tumor microenvironment; tumor-immune system interactions

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.

项目摘要： 三阴性乳腺癌（TNBC）约占侵入性乳腺癌病例的15％，不成比例 非裔美国人和西班牙裔妇女的高患病率，并由缺乏雌激素的表达来定义 受体，孕酮受体和HER2（er-/pr-/her2-）。由于当前没有目标 分子驱动因素，TNBC的治疗仍然依赖于非特异性有毒化学治疗剂和结果 贫穷的。结果，需要开发出分子信息的靶向疗法来治疗TNBC。 在此提案中，我们将MALT1蛋白酶作为TNBC子集的潜在新治疗靶靶标。 MALT1是由蛋白质Carma3，Bcl10和 MALT1（CBM信号体）在特定G蛋白偶联受体（GPCR）下游的功能驱动 在包括TNBC（TNBC）的一部分癌中进行致癌重编程。已知会激活乳腺癌的GPCR 癌症包括PAR1，AGTR1和LPARS（LPAR1-3）和这些GPCR的过表达 在实验模型中具有侵略性的乳腺癌行为，人类患者的临床结果较差。 我们最近发现GPCR/MALT1信号轴驱动了上皮到间质的程序 TNBC中的过渡（EMT）。由于已知EMT的肿瘤细胞可促进允许的免疫 抑制微环境，我们建议研究GPCR/MALT1信号轴的作用 调节肿瘤免疫微环境。我们的初步数据表明MALT1是关键的中介者 GPCR+ TNBC诱导的免疫抑制作用，表明抑制TNBC中MALT1蛋白酶活性 细胞可能具有有益的作用。另外，抑制免疫细胞中MALT1蛋白酶活性最近已有 发现优先损害Treg功能，将调节性和效应T细胞之间的平衡提高到 促进免疫反应性升高。总之，TNBC细胞和免疫细胞中的这些观察结果使我们进入 假设药物MALT1抑制作用可能在GPCR+ TNBC中具有双重治疗益处。 防止癌细胞内MALT1介导的肿瘤免疫抑制，（2）改变组成 肿瘤浸润的免疫细胞，有利于抗肿瘤免疫。该建议将通过 优雅的体外和体内模型系统的组合。我们提议的总体目标是严格 评估MALT1作为TNBC的致病驱动力的作用，并测试药物抑制作用 这种难以治疗的疾病中的新型治疗策略。