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.

项目总结 小细胞肺癌(SCLC)是肺癌中最具侵袭性的亚型，其五年生存率较低。 超过5%。免疫检查点抑制(ICI)疗法，如抗PD1/PD-L1抗体已证明 在几种难以治疗的癌症中出现了前所未有的临床活动，并在部分患者中产生了持久的反应。 例如，抗PD-L1抗体，如阿替唑单抗，最近已被FDA批准为第一批 LINE联合以铂为基础的化疗治疗小细胞肺癌；然而，疗效似乎不大。 免疫检查点抑制剂在小细胞肺癌中疗效不高的机制尚不清楚，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穷人 小细胞肺癌免疫治疗的疗效观察此外，以铂为基础的化疗对抗癌的潜在影响 肿瘤免疫反应也可能在决定免疫治疗效果方面发挥重要作用。 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，肿瘤微环境诱导免疫功能紊乱的肿瘤侵袭 DC(Tidc)，其特征是细胞内脂质含量增加和线粒体呼吸增加。这个 然而，潜在的机制在很大程度上仍不清楚。在这里，我们发现携带脂肪酸的肿瘤源自 胞外体(Exosome，TDEs)诱导免疫功能紊乱的DC促进免疫逃避。我们还发现，铂， 小细胞肺癌的一线治疗，通过重新编程，进一步加剧了TDE诱导的DC功能障碍 小细胞肺癌谷氨酰胺-脂代谢的研究从机理上讲，铂重新连接谷氨酰胺代谢以促进脂肪 酸合成，导致TDES中长链脂肪酸的丰富。因此，TIDDC利用TDEs 激活过氧化物酶体增殖物激活受体(PPAR)信号的大量脂肪酸，导致 导致脂肪异常堆积和粮农组织活性升高，最终导致 免疫抑制酶精氨酸酶1(Arg1)与TIDCs功能障碍。基因枯竭或 药物抑制PPAR有效减轻TDE诱导的树突状细胞免疫功能障碍 增强免疫疗法的疗效。这项工作揭示了TDE介导的免疫调节在 DCs，揭示PPAR位于DC代谢免疫调节的中心，提示潜在的 免疫治疗靶点。因此，靶向PPAR可以被用来改善抗癌免疫治疗。 我们将通过以下目标来验证我们的假设：目标1：探索TDEs如何激活PPAR并诱导 Arg1驱动DC功能障碍。目的2：研究铂对小细胞肺癌谷氨酰胺代谢的调节作用 导致树突状细胞功能障碍和免疫逃避。目的3：评价化疗/抗帕金森病的疗效。 L1/PPAR抑制剂联合应用于小细胞肺癌。