Platinum-induced lipid reprogramming and tumor immune microenvironment in SCLC

SCLC 中铂诱导的脂质重编程和肿瘤免疫微环境

基本信息

批准号：
10419937
负责人：
Lingtao Jin
金额：
$ 36.46万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
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/10419937
关键词：
Acute Allografting Antigen Presentation Antigen-Presenting Cells Attenuated Biological Assay Cell physiology Chronic Clinical Combination immunotherapy Combined Modality Therapy Complex Dendritic Cells Development Enzymes Exhibits Fatty Acids Functional disorder Genetic Genetically Engineered Mouse Glutamine Goals Immune Immune Evasion Immune System Diseases Immune checkpoint inhibitor Immune response Immunosuppression Immunotherapeutic agent Immunotherapy Impairment Lipids Malignant Neoplasms Malignant neoplasm of lung Mediating Mediator of activation protein Metabolic Metabolism Mitochondria Modeling Molecular Mutation Nature PD-L1 blockade Peroxisome Proliferator-Activated Receptors Pharmacology Phenotype Pilot Projects Platinum Play Proteomics Receptor Signaling Regulation Respiration Role Signal Transduction Survival Rate TP53 gene Technology Testing Therapeutic Tumor Antigens Tumor Immunity Tumor-Derived Tumor-infiltrating immune cells Validation Work antagonist anti-PD-1 anti-PD-L1 anti-PD-L1 antibodies anti-tumor immune response arginase base cancer immunotherapy checkpoint therapy chemotherapy efficacy evaluation exosome fatty acid metabolism humanized mouse immune checkpoint blockers immune function immunogenicity immunoregulation improved in vivo Model inhibitor lipid metabolism lipidomics long chain fatty acid lung small cell carcinoma metabolomics neoplasm immunotherapy patient subsets pre-clinical response therapeutic target transcriptome sequencing tumor tumor microenvironment tumor-immune system interactions uptake

项目摘要

PROJECT SUMMARY Small cell lung cancer (SCLC) is the most aggressive subtype of lung cancer with a five-year survival rate of less than 5%. Immune checkpoint inhibitor (ICI) therapy such as anti-PD1/PD-L1 antibodies has demonstrated unprecedented clinical activity in several difficult-to-treat cancers, with durable responses in a subset of patients. Anti-PD-L1 antibodies such as atezolizumab, for example, have been recently received FDA approval as first line treatment in combination with platinum-based chemotherapy for SCLC; however, the efficacy seems modest. The mechanistic basis for the modest efficacy of immune checkpoint inhibitor in SCLC remains unknown but mounting evidence suggests that the immunosuppressive nature of tumor microenvironment dictates the poor efficacy of immunotherapy in SCLC. In addition, the potential impact of platinum-based chemotherapy on anti- tumor immune response may also play an important role in determining the efficacy of immunotherapy. Dendritic cells (DCs) orchestrate the initiation, programming, and regulation of anti-tumor immune responses. Emerging evidence indicates that the tumor microenvironment induces immune dysfunctional tumor-infiltrating DC (TIDC), characterized with both increased intracellular lipid content and mitochondrial respiration. The underlying mechanism, however, remains largely unclear. Here, we found that fatty acids-carrying tumor derived exosomes (TDEs) induce immune dysfunctional DC to promote immune evasion. We also discover that platinum, the front-line treatment for SCLC, further exacerbates TDE-induced DC dysfunction through reprograming of glutamine-lipid metabolism in SCLC. Mechanistically, platinum rewires glutamine metabolism to promote fatty acid synthesis, leading to enrichment of long chain fatty acids in TDEs. As a result, TIDCs uptake TDEs with large amount of fatty acids that activates peroxisome proliferator activated receptor  (PPAR) signaling, leading to aberrant lipid accumulation and elevated FAO activity, which culminates in the induction of immunosuppressive enzyme arginase 1 (Arg1) and consequently dysfunction in TIDCs. Genetic depletion or pharmacologic inhibition of PPAR effectively attenuates TDE-induced DC-based immune dysfunction and enhances the efficacy of immunotherapy. This work uncovers a role for TDE-mediated immune modulation in DCs and reveals that PPARlies at the center of metabolic-immune regulation of DCs, suggesting a potential immunotherapeutic target. As such, targeting PPAR can be exploited to improve anti-cancer immunotherapy. We will test our hypothesis through the following aims: Aim 1: To explore how TDEs activate PPAR and induce Arg1 to drive DC dysfunction. Aim 2: To investigate how platinum rewires glutamine metabolism in SCLC to induce dendritic cell dysfunction and immune evasion. Aim 3: To evaluate the efficacy of Chemo/anti-PD- L1/PPAR inhibitor combination in SCLC.

项目概要小细胞肺癌 (SCLC) 是肺癌中最具侵袭性的亚型，五年生存率低于免疫检查点抑制剂 (ICI) 疗法（例如抗 PD1/PD-L1 抗体）已被证实。在几种难以治疗的癌症中取得了前所未有的临床活性，并在部分患者中产生了持久的反应。例如，抗 PD-L1 抗体（例如 atezolizumab）最近已作为首个获得 FDA 批准的抗体。一线治疗与铂类化疗联合治疗 SCLC；然而，疗效似乎不大。免疫检查点抑制剂对 SCLC 疗效有限的机制基础仍不清楚，但越来越多的证据表明，肿瘤微环境的免疫抑制性质决定了不良反应此外，铂类化疗对 SCLC 的潜在影响。免疫肿瘤反应也可能在决定免疫疗法的疗效方面发挥重要作用。树突状细胞 (DC) 协调抗肿瘤免疫反应的启动、编程和调节。新的证据表明肿瘤微环境会导致免疫功能失调的肿瘤浸润 DC (TIDC)，其特征是细胞内脂质含量和线粒体呼吸增加。然而，潜在的机制仍不清楚。在这里，我们发现携带脂肪酸的肿瘤衍生。外泌体（TDE）诱导免疫功能失调的 DC 促进免疫逃避。 SCLC 的一线治疗，通过重新编程进一步恶化 TDE 诱导的 DC 功能障碍 SCLC 中的谷氨酰胺-脂质代谢从机制上讲，铂重新连接谷氨酰胺代谢以促进脂肪代谢。酸合成，导致 TDE 中长链脂肪酸的富集，因此 TIDC 会吸收 TDE。大量脂肪酸可激活过氧化物酶体增殖物激活受体 α (PPARα) 信号传导，导致异常的脂质积累和FAO活性升高，最终诱导免疫抑制酶精氨酸酶 1 (Arg1) 以及因此导致的 TIDC 功能障碍。 PPARα 的药理抑制可有效减轻 TDE 诱导的基于 DC 的免疫功能障碍，增强免疫疗法的功效这项工作揭示了 TDE 介导的免疫调节的作用。 DCs 并揭示 PPARα 位于 DCs 代谢免疫调节的中心，这表明了潜在的因此，可以利用靶向 PPARα 来改善抗癌免疫治疗。我们将通过以下目标检验我们的假设：目标 1：探索 TDE 如何激活 PPARα 并诱导 Arg1 驱动 DC 功能障碍目标 2：研究铂如何重新连接 SCLC 中的谷氨酰胺代谢。诱导树突状细胞功能障碍和免疫逃避目标 3：评估化疗/抗 PD-的疗效。 SCLC 中 L1/PPARα 抑制剂组合。