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.

项目总结 近年来，在识别和治疗靶点方面有了突破性的发现。 PD-1/PD-L1免疫检查点轴。肺癌细胞表达高水平的程序性死亡配体 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，导致免疫逃逸和肿瘤进展。尽管如此 研究进展表明，PD-L1在患者体内的表达与治疗反应脱节。这 强调迫切需要了解PD-L1上调的机制，确定 抵抗PD-1/PD-L1治疗，并确定临床上需要寻求的其他免疫检查点或途径 与这种疗法相结合。为应对肿瘤微环境压力，如缺氧、血红素 在缺乏和氨基酸饥饿的情况下，癌细胞激活了综合应激反应(ISR)。ISR 激活允许癌细胞通过抑制全球蛋白质合成和 增加了精选mRNA的翻译。ISR已被证明可促进肿瘤的发生，但其作用 ISR在免疫检查点蛋白的翻译控制中的作用尚未得到充分的研究。我们最近 研究表明，ISR激活导致非小细胞肺癌(NSCLC)中PD-L1的有效诱导，并 在体外和体内抑制抗肿瘤免疫，我们有新的证据表明另一种免疫 在非小细胞肺癌细胞中，ISR激活后会产生CD155(分化簇155)检查点 与PD-L1同步。我们的中心假设是ISR激活导致肿瘤细胞免疫逃逸 通过PD-L1和CD155的翻译。在强劲的初步数据的指引下，我们将检验这一假设 通过追求三个具体目标：1)阐明ISR激活促进 CD155的翻译；2)确定ISR调制对免疫细胞反应的影响；3)检查 抑制ISR联合PD-1阻断和/或TIGIT对S免疫细胞的治疗作用 受体)在小鼠模型中被阻断。我们将采用包括荧光素酶分析在内的翻译研究。 和核糖体图谱分析ISR介导的PD-L1和CD155的翻译调控机制 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 共培养研究和免疫活性小鼠模型对ISR激活的细胞反应。最后，我们会 利用小鼠模型和ISR抑制剂确定ISR抑制是否可以通过以下方式抑制肿瘤形成 促进免疫反应以及这是否可以与现有的免疫检查点疗法协同作用 (图1，型号)。我们提出的研究具有重要意义，因为它将发现新的监管电路 管理免疫检查点蛋白的表达，2)说明癌细胞如何在 肿瘤微环境调节免疫细胞的反应，3)我们的研究将提供证据- 肺癌新的联合治疗方法的发展理念。