Long Noncoding RNA Advocates Immune Resistant Microenvironment

长非编码RNA倡导免疫抗性微环境

• 批准号: 10291060
• 负责人: Chunru Lin
• 金额: $ 37.58万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10291060
• 关键词: Address; Advocate; Antisense Oligonucleotides; Astrocytes; Attenuated; Breast Cancer Cell; Breast Cancer Patient; Breast Cancer Treatment; CD8-Positive T-Lymphocytes; Catalysis; Catalytic Domain; Cells; Clinical; Collaborations; Communities; Data; Effectiveness; Equilibrium; Future; Genetic Transcription; Goals; Heterogeneity; Human; Immune; Immunology; Immunosuppression; Immunotherapy; Infiltration; Interdisciplinary Study; Kinetics; Kynurenine; Malignant Neoplasms; Mammary gland; Mass Spectrum Analysis; Mediating; Metabolic; Metastatic Neoplasm to the Lung; Molecular; Molecular Conformation; Molecular Target; Morbidity - disease rate; Mouse Mammary Tumor Virus; Mus; Myeloid-derived suppressor cells; Nature; Oncogenic; PD-1/PD-L1; PD-L1 blockade; PVT1 gene; Parents; Pathway interactions; Pharmaceutical Preparations; Phosphorylation; Plasmacytoma; Play; Proteolysis; RAF1 gene; Research; Resistance; Role; Schwann Cells; Therapeutic; Toxic effect; Transgenic Mice; Tryptophan; Tryptophanase; Tumor Immunity; Tumor-infiltrating immune cells; Untranslated RNA; Variant; Work; base; breast cancer progression; cancer initiation; cancer type; clinical effect; combinatorial; cytotoxicity; diagnostic biomarker; effector T cell; efficacy validation; fluorocitrate; immune checkpoint; immune checkpoint blockers; immune resistance; improved; in vivo; innovation; locked nucleic acid; malignant breast neoplasm; mortality; mouse model; neoplastic cell; predictive marker; prognostic value; small molecular inhibitor; small molecule; small molecule inhibitor; success; targeted treatment; therapeutic target; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor microenvironment; tumor-immune system interactions; tumorigenesis

Project Summary Historically, the majority of relevant research has only interrogated classical pathways in breast cancer cells and has had little success in developing clinical drugs against triple-negative breast cancer (TNBC). Immunotherapy, including PD-1/PD-L1 blockade, has recently been proven effective in treating a number of tumor lineages, but the majority of TNBC cases are regarded as resistant or immune-quiescent tumors and are unresponsive to single checkpoint treatments. These challenges demand definition of the molecular mechanisms underlying the immunosuppression that develops during TNBC progression. We demonstrated that tumor-resident Schwann cells (refered as TASc) play important roles in promoting an immunosuppressive microenvironment. Tumor- resident Schwann cells express one lncRNA that modulates RAF1-mediated phosphorylation of TDO2 (Tryptophan 2,3-Dioxygenase), thereby facilitating the enzymatic activities of TDO2 and catalysis of Tryptophan (Trp) to Kynurenine (Kyn). The released Kyn in tumor microenvironment further facilitates the expansion of MDSC (myeloid-derived suppressor cells) and quiescence of effector T cells. Therefore, considering tumor- associated Schwann cell and lncRNAs as therapeutic targets may potentially sensitize TNBC to immunotherapy. The long-term goal of the proposal is to demonstrate the molecular mechanisms and functional importance of lncRNAs in breast cancer so that improved strategies can be developed to reduce TNBC morbidity and mortality. Our central hypothesis is that PVT1 facilitates phosphorylation of TDO2 in tumor-associated Schwann cells to promote triple-negative breast cancer immunoresistance, which could be attenuated in vivo using a targeted therapy. We will address our hypothesis from following aspects. 1) We will demonstrate the mechanisms of tumor-associated Schwann cell-dependent immunosuppression (Aim 1). We will determine the underlying molecular mechanisms of PVT1 in regulating the enzymatic activities of TDO2 (Aim 2). 3) We will ascertain the functional importance of tumor-resident Schwann cells and PVT1 using small molecule inhibitor and small molecular inhibitor-conjugated Pvt1 anti-sense oligonucleotides in combination with immunotherapy (Aim 3). Emerging evidence of the oncogenic involvement of lncRNAs, as well as their implicated roles in mediating immunosuppression, warrants further characterization of Schwann cell-specific lncRNAs and future applications that hinge on their activity. Our goal is to demonstrate that PVT1, expressed in tumor-associated Schwann cells, may serve as a diagnostic marker that predicts a cancer’s sensitivity to immunotherapy. Thus, a strategy that combines immune checkpoint blockers and lncRNA-based therapeutic strategies has the potential to significantly advance TNBC treatment. In the long run, these research findings will benefit the cancer community by introducing the robust clinical effects of targeting tumor-associated Schwann cells and Schwann cells-expressing lncRNAs as promising therapeutic targets.

项目摘要 从历史上看，大多数相关研究只询问了乳腺癌细胞和 在开发治疗三阴性乳腺癌(TNBC)的临床药物方面几乎没有成功。免疫疗法， 包括PD-1/PD-L1阻滞剂，最近已被证明在治疗一些肿瘤谱系方面有效，但 大多数TNBC病例被认为是耐药或免疫静止的肿瘤，对 单一检查站治疗。这些挑战要求对潜在的分子机制进行定义 在TNBC进展过程中出现的免疫抑制。我们证明了肿瘤居住者施万恩 细胞(简称TASC)在促进免疫抑制微环境中起着重要作用。肿瘤- 常驻雪旺细胞表达一种调节RAF1介导的TDO2磷酸化的lncRNA (色氨酸2，3-双加氧酶)，从而促进TDO2的酶活性和色氨酸的催化 (Trp)为犬尿氨酸(Kyn)。肿瘤微环境中释放的Kyn进一步促进肿瘤的扩张 MDSC(髓系来源的抑制细胞)和效应T细胞的静止。因此，考虑到肿瘤- 相关的雪旺细胞和lncRNAs作为治疗靶点可能会使TNBC对免疫治疗敏感。 该提案的长期目标是证明分子机制和功能的重要性。 因此，可以制定改进的策略，以降低TNBC的发病率和死亡率。 我们的中心假设是PVT1促进肿瘤相关雪旺细胞中TDO2的磷酸化，以 促进三阴性乳腺癌免疫耐药，这可以在体内使用靶向减弱 心理治疗。我们将从以下几个方面来阐述我们的假设。1)我们将演示 肿瘤相关的雪旺细胞依赖性免疫抑制(目标1)。我们将确定潜在的 PVT1调节TDO2酶活性的分子机制(目标2)。3)我们会确定 小分子抑制剂和Small联合应用对肿瘤许旺细胞和PVT1功能的重要性 分子抑制物结合PVT1反义寡核苷酸联合免疫治疗(目标3)。 关于lncRNAs参与致癌的新证据，以及它们在调节中的作用 免疫抑制--雪旺细胞特异性lncRNAs的进一步表征及未来应用 这取决于他们的活动。我们的目标是证明在肿瘤相关的雪旺细胞中表达的PVT1， 可以作为一种诊断标记物，预测癌症对免疫疗法的敏感性。因此，一种战略， 结合免疫检查点阻滞剂和基于lncRNA的治疗策略有可能显著 推进TNBC治疗。从长远来看，这些研究成果将使癌症社区受益 介绍靶向肿瘤相关雪旺细胞和雪旺细胞表达的强大临床效果 LncRNAs作为有希望的治疗靶点。