Immunometabolic pathways enabled by PARP inhibition in breast cancer

项目总结 肿瘤相关巨噬细胞(TAMs)在实体瘤中含量丰富，并促进肿瘤的发生和耐药 去接受治疗。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)，推动了 通过代谢重塑和诱导脂肪生成抑制T-TAMs的发展 细胞的激活和功能。相反，用PARPI处理的T细胞表现出生物能量的适应性，优越的生存能力- 以及增强的效应器功能。尽管人们热衷于将PARPI与免疫检查点相结合 基于每类药物对T细胞激活的潜在协同作用的阻滞剂(ICB)，早期临床试验 还没有证明联合治疗优于PARPI单一治疗，建议使用促脂肪的TAMS 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，以产生有害的TAMs，同时促进优越的抗肿瘤T细胞。在缺席时 没有这样的知识，成功的战略来利用PARPI的力量造福癌症患者是不可能的。 长期目标是通过的调制，设计临床有效的策略，促进T细胞的激活。 改善和减弱免疫抑制的TME，以提高乳腺癌患者的治疗水平。中央高铁- 假说是，造脂的TAMs部分通过抑制T细胞促进肿瘤的发生，并由 PARPI疗法，为增强PARPI+ICB提供了独特的治疗机会。总体目标是 目的：(1)了解在急性呼吸窘迫综合征(PARPI)中的特点及T细胞代谢调节；(2)确定临床有效策略。 调节代谢，增强T细胞活化和PARPI反应。中心假说 将通过追求以下特定目的来检验：1)确定造脂巨噬细胞去脂的机制 发展。人和小鼠单核细胞和巨噬细胞将被用来正式定义的脂肪生成 PARPI的催化作用及TnBC诱导脂肪生成机制的研究 使用无偏见的脂质组学和功能研究。2)检测致脂性TAMs促进肿瘤发生 通过抑制PARPI介导的适应性免疫代谢重塑。AIM 2将聘用 体外和体内蛋白质合成、蛋白质组学和代谢组学分析PARPI如何诱导T细胞 代谢适合度和确定抗肿瘤治疗的最佳代谢扰动。3)确定最优 PARPI和代谢重塑快速转化为乳腺癌患者的治疗策略。 多个TNBC小鼠模型将被用来测试TAMS的耗尽是否为具有免疫缺陷的T细胞扫清了道路。 事实证明，PARPI、新陈代谢重塑或这些疗法的组合形成了生物能量健身。独一无二 PARPI和PARPI+ICB治疗患者的临床试验样本将使用最先进的技术进行评估， 单细胞成像以确定免疫表型和功能。成功完成将揭示小说Thera- 规避造脂TAMs同时激活代谢优势抗肿瘤的治疗策略 T细胞，并具有快速临床转化的潜力，以提高PARPI+ICB治疗的有效性。

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.