Immune Checkpoint Regulation by the Integrated Stress Response Pathway in Lung Ca

肺钙综合应激反应途径的免疫检查点调节

• 批准号: 10678603
• 负责人: Shayna Thomas-Jardin
• 金额: $ 6.95万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10678603
• 关键词: 5' Untranslated Regions; Amino Acids; Biological Assay; Cancer Etiology; Cancer Patient; Cell Proliferation; Cell Survival; Cell physiology; Cells; Cessation of life; Clinical; Coculture Techniques; Data; Dendritic Cells; Development; Environment; Eukaryotic Initiation Factors; Heme; Hypoxia; ITIM; Immune; Immune Cell Suppression; Immune response; Immunocompetent; In Vitro; Ligands; Luciferases; Lung; Malignant Neoplasms; Malignant neoplasm of lung; Measures; Mediating; Mediator; Membrane Glycoproteins; Messenger RNA; Modeling; Monoclonal Antibodies; Mus; Natural Killer Cells; Nature; Non-Small-Cell Lung Carcinoma; Oncogenic; Open Reading Frames; Osmosis; Outcome; PD-1 blockade; Pathway interactions; Patients; Phosphorylation; Phosphotransferases; Population; Prokaryotic Initiation Factor-2; Protein Biosynthesis; Proteins; Receptor Cell; Recurrence; Regulation; Reporter; Research; Role; Solid Neoplasm; Starvation; Stimulus; Stress; T-Cell Receptor; T-Lymphocyte; Testing; Therapeutic; Translations; Treatment Efficacy; Tumor Immunity; Tumor Promotion; Tumor-infiltrating immune cells; Up-Regulation; Work; arm; biological adaptation to stress; cancer cell; checkpoint therapy; deprivation; endoplasmic reticulum stress; experience; fitness; heme biosynthesis; humanized mouse; immune checkpoint; immune checkpoint blockade; in vivo; inhibitor; lung cancer cell; mouse model; neoplastic cell; new combination therapies; polysome profiling; programmed cell death ligand 1; programmed cell death protein 1; protein expression; receptor; resistance mechanism; response; ribosome profiling; synergism; targeted treatment; therapeutic target; therapy resistant; translational study; treatment response; tumor; tumor microenvironment; tumor progression; tumorigenesis

PROJECT SUMMARY In recent years, there have been groundbreaking discoveries in the identification and therapeutic targeting of the PD-1/PD-L1 immune checkpoint axis. Lung cancer cells express high levels of Programmed Death Ligand 1 (PD-L1), a critical ligand for PD-1 on T cells. The PD-1/PD-L1 interaction allows tumor cells to directly suppress anti-tumor T cell activity, resulting in immune escape and tumor progression. Despite these advances, there remains a disconnect in patient expression of PD-L1 and treatment response. This underscores the critical need to understand mechanisms of PD-L1 upregulation, identify mechanisms of resistance to PD-1/PD-L1 therapy, and identify other immune checkpoints or pathways to pursue clinically in combination with this therapy. In response to tumor microenvironment stresses, such as hypoxia, heme deprivation, and amino acid starvation, cancer cells activate the integrated stress response (ISR). ISR activation allows cancer cells to escape these stresses through inhibition of global protein synthesis and increased translation of select mRNAs. The ISR has been shown to promote tumorigenesis, yet the role of the ISR in the translational control of immune checkpoint proteins has not been fully investigated. We recently demonstrated that ISR activation leads to potent induction of PD-L1 in non-small cell lung cancer (NSCLC) and suppression of anti-tumor immunity in vitro and in vivo, and we have new evidence that another immune checkpoint, CD155 (Cluster of differentiation 155), is induced upon ISR activation in NSCLC cells simultaneously with PD-L1. Our central hypothesis is that ISR activation causes tumor cell immune escape through translation of both PD-L1 and CD155. Guided by strong preliminary data, we will test this hypothesis by pursuing three specific aims: 1) Elucidate the mechanisms through which ISR activation promotes translation of CD155; 2) Determine the effect of ISR modulation on immune cell responses; 3) Examine the therapeutic efficacy of ISR inhibition in combination with PD-1 blockade and/or TIGIT (CD155’s immune cell receptor) blockade in mouse models. We will employ translational studies including luciferase reporter assays and ribosome profiling to dissect the mechanisms of ISR mediated PD-L1 and CD155 translational control in NSCLC cells. To determine the impact of ISR activation on immune cell responses, we will measure immune cell responses in co-culture studies and immunocompetent mouse models upon ISR activation. Finally, we will utilize mouse models and ISR inhibitors to determine whether ISR inhibition can suppress tumorigenesis by promoting an immune response and whether this can synergize with existing immune checkpoint therapies (Fig 1, model). Our proposed research is significant, because it will 1) uncover new regulatory circuits that govern immune checkpoint protein expression, 2) illuminate how insults experienced by cancer cells in the tumor microenvironment modulate the responses of immune cells, and 3) our studies will provide proof-of- concept for the development of new combination therapies for lung cancer.

项目摘要 近年来，在识别和治疗靶向方面存在着突破性的发现 PD-1/PD-L1免疫检查点轴。肺癌细胞表达高水平的编程死亡配体 1（PD-L1），T细胞上PD-1的关键配体。 PD-1/PD-L1相互作用允许肿瘤细胞直接 抑制抗肿瘤T细胞活性，导致免疫逃生和肿瘤进展。尽管如此 进步，PD-L1的患者表达和治疗反应仍存在断开连接。这 强调了解PD-L1上调机制的迫切需要，确定机制 对PD-1/PD-L1治疗的耐药性，并确定其他免疫检查点或临床纯的途径 结合这种疗法。响应肿瘤微环境应力，例如缺氧，血红素 剥夺和氨基酸饥饿，癌细胞激活综合应力反应（ISR）。 ISR 激活使癌细胞通过抑制全球蛋白质合成和 选择的mRNA翻译增加。 ISR已被证明可以促进肿瘤发生，但是 ISR在免疫光切蛋白的翻译控制中尚未得到充分研究。我们最近 证明ISR激活导致在非小细胞肺癌（NSCLC）和 体外和体内抑制抗肿瘤免疫学，我们有新的证据表明另一种免疫学 检查点CD155（分化155的簇）在NSCLC细胞中诱导ISR激活后诱导 与PD-L1相似。我们的中心假设是ISR激活导致肿瘤细胞免疫逃生 通过PD-L1和CD155的翻译。在强大的初步数据的指导下，我们将检验此假设 通过追求三个具体目标：1）阐明ISR激活促进的机制 CD155的翻译； 2）确定ISR调节对免疫细胞反应的影响； 3）检查 ISR抑制的治疗效率与PD-1封锁和/或Tigit（CD155的免疫细胞）结合使用 鼠标模型中的接收器）。我们将采用翻译研究，包括荧光素酶报告基准测定法 和核糖体分析，以剖析ISR介导的PD-L1和CD155转化的机制 NSCLC细胞。为了确定ISR激活对免疫细胞反应的影响，我们将测量免疫 ISR激活后共培养研究和免疫能力小鼠模型中的细胞反应。最后，我们会的 利用小鼠模型和ISR抑制剂来确定ISR抑制是否可以通过 促进免疫反应，以及是否可以与现有的免疫检查点疗法协同作用 （图1，模型）。我们提出的研究很重要，因为它将1）揭示新的监管电路 管理免疫切除点蛋白表达，2）阐明癌细胞在 肿瘤微环境调节免疫细胞的反应，3）我们的研究将提供证明 开发肺癌新组合疗法的概念。