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

• 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
• 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

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.

项目摘要 小细胞肺癌（SCLC）是肺癌最具侵略性的亚型，生存率较低 超过5％。免疫检查点抑制剂（ICI）疗法，例如抗PD1/PD-L1抗体已证明 几种难以治疗的癌症中前所未有的临床活动，一部分患者的反应持久。 例如 线路处理与SCLC的基于铂的化学疗法结合；但是，效率似乎不大。 SCLC中免疫切克点抑制剂适度效率的机械基础仍然未知，但是 越来越多的证据表明，肿瘤微环境的免疫抑制性质决定了穷人 免疫疗法在SCLC中的功效。此外，基于铂的化学疗法对抗 - 的潜在影响 肿瘤免疫激素也可能在确定免疫疗法的效率中起重要作用。 树突状细胞（DCS）协调抗肿瘤免疫反应的主动性，编程和调节。 新兴的证据表明，肿瘤微环境诱导免疫功能障碍肿瘤功能失调 DC（TIDC）的特征是细胞内脂质含量增加和线粒体呼吸。这 然而，基本的机制仍然在很大程度上不清楚。在这里，我们发现衍生出脂肪酸的肿瘤 外泌体（TDE）诱导免疫功能失调的直流，以促进免疫逃避。我们还发现白金， SCLC的前线处理，进一步加剧了TDE诱导的直流功能障碍 SCLC中的谷氨酰胺脂质代谢。从机械上讲，铂恢复谷氨酰胺代谢以促进脂肪 酸合成，导致长链脂肪酸在TDE中富集。结果，tidcs吸收tdes 激活过氧化物组增殖物激活受体（PPAR）信号的大量脂肪酸，领先 使脂质的累积和粮农组织活性升高，这是在诱导中的最终 免疫抑制酶精氨酸酶1（ARG1），因此在TIDC中功能障碍。遗传耗竭或 PPAR的药理抑制有效地减弱了TDE诱导的基于DC的免疫功能障碍和 提高免疫疗法的效率。这项工作发现了TDE介导的免疫调节的作用 DC并揭示了DC代谢免疫调节中心的PPARLIES，这表明潜力 免疫治疗靶标。因此，可以探索靶向PPAR以改善抗癌免疫疗法。 我们将通过以下目的测试我们的假设：目标1：探索TDE如何激活PPAR并影响 ARG1驱动直流功能障碍。目标2：研究铂是如何将SCLC中的谷氨酰胺代谢的重新解散为 诱导树突状细胞功能障碍和免疫进化。目标3：评估化学/抗PD-的效率 SCLC中的L1/PPAR抑制剂组合。