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: 10649673
• 负责人: Jennifer L. Guerriero
• 金额: $ 46.39万
• 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/10649673
• 关键词: 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; Combined Modality Therapy; Cytotoxic T-Lymphocytes; DNA Damage; Data; Dependence; Development; Effectiveness; Equipoise; Excision; Exhibits; Goals; Human; Immune; Immunotherapy; In Vitro; Knowledge; Lead; Lipids; Macrophage; Mammary Neoplasms; Mediating; Metabolic; Metabolism; Mus; Neoplasm Metastasis; Nutrient; Outcome; Oxygen; PARP inhibition; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Poly(ADP-ribose) Polymerase Inhibitor; 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; cancer therapy; cancer type; cellular imaging; chemotherapy; clinical translation; design; early phase clinical trial; early phase trial; fitness; immune checkpoint blockade; improved; in vivo; inhibitor therapy; lipid biosynthesis; lipidomics; 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.

项目摘要 肿瘤相关的巨噬细胞（TAM）在实体瘤中丰富，并驱动肿瘤发生和抗性 接受治疗。令人惊讶的是，一种常用的癌症药物，聚（ADP-核糖）聚合酶抑制剂（PARPI），驱动 通过代谢重塑和诱导脂肪生成来发展抑制性TAM，这限制了T- 细胞激活和功能。相反，用PARPI处理的T细胞表现出生物能适应性，优质 ITY和效应函数增强。虽然有热情将PARPI与免疫检查站相结合 封锁（ICB），基于每类药物的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响应。因此，迫切需要阐明parpi诱导的二分法 代谢重塑以产生有害的TAM，同时促进上抗肿瘤的T细胞。在缺席的情况下 在这种知识的成功策略中，不太可能利用PARPI使PARPI受益的力量。 长期目标是通过TAM调节设计具有临床有效策略，以促进T细胞Activa- 削弱并削弱免疫抑制性TME，以改善乳腺癌患者的治疗。中央 pothesis是，脂肪生成TAMS部分通过T细胞抑制作用促进肿瘤发生，并被催化 PARPI疗法，为增强Parpi + ICB提供独特的治疗机会。总体目标是 （i）表征PARPI期间TAM和T细胞代谢调节的特征，并且（ii）确定临床有效的层 主管TAM代谢以增强T细胞激活和PARPI响应的主体。中心假设 将通过追求以下特定目的来测试：1）定义脂肪生成巨噬细胞的机制 速度。人和鼠的单核细胞和巨噬细胞将用于正式定义TAM脂肪形成 由PARPI催化并确定TNBC治疗期间诱导TAM脂肪形成的机制 使用公正的脂肪组和功能研究。 2）测试脂肪生成TAMS促进肿瘤发生 通过抑制PARPI介导的自适应免疫的代谢重塑。 AIM 2将使用 体外和体内蛋白质合成，蛋白质组学和代谢组学分析，以详细说明PARPI如何诱导T细胞 代谢适应性并定义用于抗肿瘤疗法的最佳代谢扰动。 3）确定最佳 快速转化为乳腺癌患者的PARPI和代谢重塑的治疗策略。 将采用多种TNBC小鼠模型来测试TAM的耗竭是否清除了具有IM-的T细胞的路径 被证明是由PARPI，代谢重塑或疗法组合而成的生物能健身。独特的 将使用最先进的ART评估接受PARPI和PARPI + ICB患者的临床试验样本。 单细胞成像以识别免疫表型和功能。成功完成将揭示新颖的thera- 同时激活代谢上优质抗肿瘤的脂肪生成TAM的精致策略 T细胞具有快速临床翻译的潜力，可以提高PARPI + ICB治疗的有效性。