Molecular Mechanisms of Bladder Cancer Immunometabolism

膀胱癌免疫代谢的分子机制

• 批准号: 10584835
• 负责人: Jianjun Gao
• 金额: $ 50.89万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2028-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10584835
• 关键词: Antibodies; Antisense Oligonucleotides; Astrocytes; Attenuated; Biology; Bladder; Cancer Model; Cancer Patient; Catalysis; Cells; Clinical; Collaborations; Communities; Data; Disease; Dissociation; Effectiveness; Equilibrium; Future; Goals; Human; Immune; Immune checkpoint inhibitor; Immunologic Cytotoxicity; Immunosuppression; Immunotherapeutic agent; Immunotherapy; Infiltration; Interdisciplinary Study; Interleukin-6; Kinetics; Knockout Mice; Kynurenine; Kynurenine-oxoglutarate aminotransferase; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Mediating; Metabolic; Modeling; Molecular; Mus; Myeloid-derived suppressor cells; Neoplasm Metastasis; Oncogenic; PD-1/PD-L1; PD-L1 blockade; Pathway interactions; Patients; Pharmaceutical Preparations; Phosphorylation; Platinum; Play; Production; RAF1 gene; Reagent; Research; Resistance; Role; Schwann Cells; Signal Transduction; Therapeutic; Tissues; Toxic effect; Tryptophan; Tryptophanase; Tumor Immunity; Tumor Promotion; Tumor Tissue; Tumor-infiltrating immune cells; Untranslated RNA; Work; antagonist; anti-PD-1; anti-PD-L1 antibodies; bioinformatics tool; cancer cell; cancer therapy; checkpoint therapy; clinical effect; combinatorial; design; effector T cell; fluorocitrate; immune checkpoint; immune resistance; immunoregulation; improved; in vivo; inhibitor; innovation; kynurenine aminotransferase II; locked nucleic acid; neoplastic cell; neutralizing antibody; novel; novel strategies; plasmacytoma variant translocation gene 1; prognostic value; response; small molecule; small molecule inhibitor; success; targeted treatment; therapeutic RNA; therapeutic target; tumor; tumor growth; tumor microenvironment; tumor progression; tumor-immune system interactions; tumorigenesis

Project Summary Historically, the majority of relevant research has only interrogated classical pathways in bladder cancer cells and has had little success in developing clinical drugs against bladder cancer (BC). Immunotherapy, including PD-1/PD-L1 blockade, has recently been proven effective in treating a number of tumor lineages, but the majority of BC 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 immuno- suppression that develops during BC progression. We demonstrated that tumor-resident Schwann cells (referred as TASc) play important roles in promoting an immunosuppressive microenvironment. TAScs 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 to Kynurenine. The released Kynurenine in tumor microenvironment further facilitates the expansion of MDSC (myeloid-derived suppressor cells) and quiescence of effector T cells. Therefore, considering TAScs and lncRNAs as therapeutic targets may potentially sensitize BC to immunotherapy. The long-term goal of the proposal is to demonstrate the molecular mechanisms and functional importance of lncRNAs in BC so that improved strategies can be developed to reduce BC immune resistance. Our central hypothesis is that PVT1 facilitates phosphorylation of TDO2 in TAScs to promote BC immunoresistance, which could be attenuated in vivo using a targeted therapy. We will address our hypothesis from following aspects. 1) We will demonstrate the prognostic value of TAScs in BC and determine the functional importance of TASc expressing lncRNA in BC tumorigenesis (Aim 1). We will determine the underlying molecular mechanisms of lncRNA in regulating the enzymatic activities of TDO2 and the IL-6 induced, RAF1-mediated phosphorylation of TDO2 (Aim 2). 3) We will ascertain the functional importance of TAScs using small molecule inhibitor and small molecule inhibitor-conjugated anti-sense oligonucleotides, anti-IL-6 neutralization antibody, or kynurenine aminotransferase inhibitor in combination with immunotherapy in inhibiting BC immune resistance and metastasis (Aim 3). Emerging evidence of the oncogenic involvement of lncRNAs, as well as their implicated roles in mediating immunosuppression, warrants further characterization of TASc-specific lncRNAs and future applications that hinge on their activity. Our goal is to demonstrate the underlying mechanisms of BC immune resistance from lncRNA and metabolite points of view. Thus, a strategy that combines immune checkpoint inhibitors and lncRNA- based therapeutic strategies has the potential to significantly advance BC treatment. In the long run, these research findings will benefit the cancer community by introducing the robust clinical effects of targeting TAScs and TASc-expressing lncRNAs as promising therapeutic targets.

项目摘要 从历史上看，大多数相关研究仅询问膀胱癌细胞中的经典途径 并且在开发针对膀胱癌（BC）的临床药物方面几乎没有成功。免疫治疗，包括 PD-1/PD-L1阻断剂最近已被证明在治疗许多肿瘤谱系中有效，但大多数肿瘤谱系是恶性的。 的BC病例被认为是耐药或免疫静止肿瘤，对单个检查点无反应 治疗。这些挑战需要定义免疫相关的分子机制， 在BC进展过程中出现的抑制。我们证明，肿瘤驻留的雪旺细胞（参考 如TASc）在促进免疫抑制微环境中起重要作用。TAScs Express 1 lncRNA调节RAF 1介导的TDO 2（色氨酸2，3-双加氧酶）磷酸化，从而 促进TDO 2的酶活性和色氨酸催化成犬尿氨酸。释放的犬尿氨酸 在肿瘤微环境中进一步促进MDSC（髓源性抑制细胞）的扩增， 效应T细胞的静止。因此，将TAScs和lncRNA作为治疗靶点可能会有潜在的 使BC对免疫疗法敏感。 该提案的长期目标是证明的分子机制和功能的重要性， BC中的lncRNA，以便可以开发改进的策略来降低BC免疫抗性。我们的中央 假设PVT 1促进TAScs中TDO 2的磷酸化以促进BC免疫抗性， 可以在体内使用靶向治疗来减弱。我们将从以下几个方面来验证我们的假设。第一章 我们将证明TASc在BC中的预后价值，并确定TASc的功能重要性。 在BC肿瘤发生中表达lncRNA（Aim 1）。我们将确定潜在的分子机制， lncRNA在调节TDO 2的酶活性和IL-6诱导的RAF 1介导的TDO 2磷酸化中的作用 TDO 2（目标2）。3)我们将使用小分子抑制剂和小分子抑制剂来确定TAScs的功能重要性。 分子标记物缀合的反义寡核苷酸、抗IL-6中和抗体或犬尿氨酸 氨基转移酶抑制剂与免疫疗法组合抑制BC免疫抵抗， 转移（目的3）。 新出现的证据表明lncRNA参与致癌，以及它们在介导肿瘤发生中的作用。 免疫抑制，保证进一步表征TASC特异性lncRNA和未来的应用， 取决于它们活动。我们的目标是证明BC免疫抵抗的潜在机制， lncRNA和代谢物的观点。因此，结合免疫检查点抑制剂和lncRNA- 的治疗策略有可能显着推进BC治疗。从长远来看，这些 研究结果将通过引入靶向TAScs的强大临床效果而使癌症社区受益 和表达TASC的lncRNA作为有希望的治疗靶点。