Immunometabolic pathways enabled by PARP inhibition in breast cancer

项目摘要 肿瘤相关巨噬细胞（tumor associated macrophages，TAMs）在实体瘤中大量存在，并驱动肿瘤发生和耐药 接受治疗引人注目的是，一种常用的癌症药物，聚（ADP-核糖）聚合酶抑制剂（PARPi）， 通过代谢重塑和诱导限制T- 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，上级活性， 和增强的效应器功能。虽然人们热衷于将PARPi与免疫检查点结合起来 阻断（ICB），基于每类药物的T细胞活化的潜在协同作用，早期临床试验 尚未证明联合治疗优于PARPi单药治疗，表明产脂TAM 可能会限制PARPi + ICB响应。因此，迫切需要阐明PARPi诱导的 代谢重塑以产生有害的TAM，同时促进上级抗肿瘤T细胞。在没有 利用PARPi的力量使癌症患者受益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，以促进T细胞活化。 因此，我们认为，TME可以通过抑制和削弱免疫抑制性TME来改善乳腺癌患者的治疗。中央卫生- 一种假设是，脂肪生成性TAM部分通过T细胞抑制促进肿瘤发生，并由 PARPi疗法，提供了一个独特的治疗机会，以加强PARPi + ICB。总体培养目标是 （i）表征PARPi期间的TAM和T细胞代谢调节，和（ii）确定临床有效的策略， 例如，调节TAM代谢以增强T细胞活化和PARPi反应。核心假设 本研究将从以下几个方面进行探讨：1）阐明巨噬细胞去脂的机制; - 谢谢人和鼠单核细胞和巨噬细胞将用于正式定义TAM脂肪生成 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TAM促进肿瘤发生 通过抑制PARPi介导的获得性免疫的代谢重塑。目标2将采用 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治疗的最佳代谢扰动。3)确定最佳 PARPi和代谢重塑的治疗策略，以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缺陷的T细胞清除了路径。 通过PARPi、代谢重塑或组合疗法形成的已证明的生物能量健身。独特 来自PARPi和PARPi + ICB治疗患者的临床试验样品将使用最新技术水平进行评估， 单细胞成像以鉴定免疫表型和功能。成功的完成将揭示新的治疗- 避免脂肪生成TAM同时激活代谢上优越的上级抗肿瘤药物的治疗策略 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.