Immunometabolic pathways enabled by PARP inhibition in breast cancer

乳腺癌中 PARP 抑制启用的免疫代谢途径

• 批准号: 10417531
• 负责人: Jennifer L. Guerriero
• 金额: $ 47.05万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10417531
• 关键词: Address; Antineoplastic Agents; Antitumor Response; Bioenergetics; Breast Cancer Patient; Breast Cancer Treatment; Breast Oncology; CD8-Positive T-Lymphocytes; Cancer Patient; Cell Survival; Cell physiology; Cells; Cellular Metabolic Process; Cellular biology; Clinical; Clinical Trials; Cytotoxic T-Lymphocytes; DNA Damage; Data; Dependence; Development; Duct (organ) structure; Effectiveness; Equipoise; Excision; Exhibits; Goals; HMGA2 gene; Human; Immune; Immune checkpoint inhibitor; Immuno-Chemotherapy; In Vitro; Knowledge; Lead; Lipids; Mammary Neoplasms; Mediating; Metabolic; Metabolism; Mus; Neoplasm Metastasis; Nutrient; Outcome; Oxygen; PARP inhibition; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Poly(ADP-ribose) Polymerases; Positioning Attribute; Protein Biosynthesis; Proteomics; Regulation; Research; Resistance; SRE-1 binding protein; Sampling; Solid Neoplasm; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Tissues; Translations; Treatment Efficacy; Tumor-associated macrophages; Work; adaptive immunity; angiogenesis; base; cancer therapy; cancer type; cellular imaging; clinical translation; design; early phase clinical trial; early phase trial; fitness; immune checkpoint blockade; improved; in vivo; inhibitor; inhibitor therapy; lipid biosynthesis; lipidomics; macrophage; malignant breast neoplasm; metabolic fitness; metabolomics; monocyte; mouse model; next generation; novel; novel therapeutic intervention; optimal treatments; programs; recruit; response; success; synergism; therapy resistant; trait; treatment response; treatment strategy; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor microenvironment; tumorigenesis

PROJECT SUMMARY Tumor associated macrophages (TAMs) are abundant in solid tumors and drive tumorigenesis and resistance to therapy. Strikingly, a commonly used cancer drug, poly (ADP-ribose) polymerase inhibitors (PARPi), drive development of suppressive TAMs through metabolic remodeling and induction of lipogenesis that restrict T- cell activation and function. Conversely, T-cells treated with PARPi exhibit bioenergetic fitness, superior viabil- ity, and heightened effector function. While there is enthusiasm for combining PARPi with immune checkpoint blockade (ICB), based on potential synergy of T-cell activation of each class of drug, early phase clinical trials have not yet demonstrated the combination to be superior to PARPi monotherapy, suggesting lipogenic TAMs may limit PARPi + ICB responses. Thus, there is a critical need to elucidate the dichotomy of PARPi-induced metabolic remodeling to generate deleterious TAMs while promoting superior antitumor T-cells. In the absence of such knowledge successful strategies to harness the power of PARPi to benefit cancer patients are unlikely. The long-term goal is to design clinically effective strategies through TAM modulation to promote T-cell activa- tion and weaken the immune-suppressive TME to improve therapy in breast cancer patients. The central hy- pothesis is that lipogenic TAMs promote tumorigenesis in part through T-cell inhibition and are catalyzed by PARPi therapy, offering a unique therapeutic opportunity to enhance PARPi + ICB. The overall objectives are to (i) characterize TAM and T-cell metabolic regulation during PARPi and (ii) determine clinically effective strat- egies to regulate TAM metabolism to enhance T-cell activation and PARPi responses. The central hypothesis will be tested by pursing the following specific aims: 1) Define the mechanism of lipogenic macrophage de- velopment. Human and murine monocytes and macrophages will be used to formally define TAM lipogenesis catalyzed by PARPi and determine the mechanism by which TAM lipogenesis is induced during TNBC therapy using unbiased lipidomic as well as functional studies. 2) Test that lipogenic TAMs promote tumorigenesis through suppression of PARPi-mediated metabolic remodeling of adaptive immunity. Aim 2 will employ in vitro and in vivo protein synthesis, proteomics and metabolomic analysis to detail how PARPi induces T-cell metabolic fitness and define optimal metabolic perturbation for anti-tumor therapy. 3) Determine the optimal treatment strategy of PARPi and metabolic remodeling for rapid translation to breast cancer patients. Multiple TNBC mouse models will be employed to test if depletion of TAMs clears a path for T-cells with im- proved bioenergetic fitness fashioned by PARPi, metabolic remodeling, or the therapies combined. Unique clinical trial samples from patients treated with PARPi and PARPi + ICB will be assessed using state-of-the-art, single cell imaging to identify immune phenotype and function. Successful completion will reveal novel thera- peutic strategies to circumvent lipogenic TAMs while simultaneously activating metabolically superior antitumor T-cells and has potential for rapid clinical translation to increase the effectiveness of PARPi + ICB therapy.

项目概要 肿瘤相关巨噬细胞 (TAM) 在实体瘤中含量丰富，可驱动肿瘤发生和耐药 来治疗。引人注目的是，一种常用的抗癌药物聚（ADP-核糖）聚合酶抑制剂（PARPi）可驱动 通过限制 T- 的代谢重塑和诱导脂肪生成来发展抑制性 TAM 细胞活化和功能。相反，用 PARPi 处理的 T 细胞表现出生物能适应性、优越的生存能力 性和增强的效应器功能。虽然人们对将 PARPi 与免疫检查点结合起来充满热情 封锁（ICB），基于每类药物T细胞激活的潜在协同作用，早期临床试验 尚未证明该组合优于 PARPi 单一疗法，表明脂肪生成 TAM 可能会限制 PARPi + ICB 反应。因此，迫切需要阐明 PARPi 诱导的二分法 代谢重塑产生有害的 TAM，同时促进优质的抗肿瘤 T 细胞。在缺席的情况下 如果没有这些知识，利用 PARPi 的力量造福癌症患者的成功策略是不可能的。 长期目标是通过TAM调节设计临床有效的策略来促进T细胞激活 化并削弱免疫抑制 TME，以改善乳腺癌患者的治疗。中央hy- 假设脂肪生成 TAM 部分通过 T 细胞抑制促进肿瘤发生，并由以下物质催化： PARPi 疗法，提供了增强 PARPi + ICB 的独特治疗机会。总体目标是 (i) 描述 PARPi 期间 TAM 和 T 细胞代谢调节的特征，以及 (ii) 确定临床有效的策略 例如调节 TAM 代谢以增强 T 细胞激活和 PARPi 反应。中心假设 将通过追求以下具体目标进行测试：1）定义脂肪生成巨噬细胞脱脂的机制 发展。人类和小鼠单核细胞和巨噬细胞将用于正式定义 TAM 脂肪生成 由 PARPi 催化并确定 TNBC 治疗期间诱导 TAM 脂肪生成的机制 使用公正的脂质组学和功能研究。 2) 测试脂肪生成TAMs促进肿瘤发生 通过抑制 PARPi 介导的适应性免疫代谢重塑。目标 2 将雇用 体外和体内蛋白质合成、蛋白质组学和代谢组学分析，详细说明 PARPi 如何诱导 T 细胞 代谢适应性并定义抗肿瘤治疗的最佳代谢扰动。 3）确定最优 PARPi 和代谢重塑的治疗策略可快速转化为乳腺癌患者。 将采用多个 TNBC 小鼠模型来测试 TAM 的消耗是否为具有免疫抑制作用的 T 细胞扫清了道路。 已证明通过 PARPi、代谢重塑或联合疗法形成的生物能量健康。独特的 来自接受 PARPi 和 PARPi + ICB 治疗的患者的临床试验样本将使用最先进的、 单细胞成像以确定免疫表型和功能。成功完成将揭示新颖的疗法 规避脂肪生成 TAM，同时激活代谢优越的抗肿瘤作用的治疗策略 T 细胞，具有快速临床转化的潜力，可提高 PARPi + ICB 疗法的有效性。