Molecular Mechanisms of Bladder Cancer Immunometabolism

膀胱癌免疫代谢的分子机制

基本信息

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
项目类别：
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

项目摘要

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，大多数相关研究仅质疑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。免疫疗法，包括 PD-1/PD-L1封锁最近已被证明有效治疗多个肿瘤谱系，但大多数卑诗省病例被认为是抗性或免疫的肿瘤，对单个检查点没有反应治疗。这些挑战要求对免疫的分子机制定义在BC进展过程中发展的抑制。我们证明了肿瘤居民雪旺细胞（引用作为TASC）在促进免疫抑制微环境中起着重要作用。 TASCS表达一个 lncRNA调节raf1介导的TDO2（色氨酸2,3-二氧酶）的磷酸化）促进TDO2的酶促活性和色氨酸催化为Kynurenine。释放的kynurenine 在肿瘤中，微环境进一步促进了MDSC（髓样衍生的抑制细胞）和效应T细胞的静止。因此，将TASC和LNCRNA视为治疗目标将BC敏感到免疫疗法。该提案的长期目标是证明分子机制和功能重要性 BC中的LNCRNA，因此可以开发改进的策略来降低BC免疫抵抗力。我们的中心假设是PVT1促进了TASC中TDO2的磷酸化，以促进BC免疫抗性，这可以使用靶向疗法在体内减弱。我们将从以下方面解决我们的假设。 1）我们将证明tascs在卑诗省的预后价值，并确定TASC的功能重要性在BC肿瘤发生中表达LNCRNA（AIM 1）。我们将确定的基本分子机制 LNCRNA调节TDO2的酶活性和IL-6诱导的RAF1介导的磷酸化的酶促活性 TDO2（AIM 2）。 3）我们将使用小分子抑制剂和小型TASC确定TASC的功能重要性分子抑制剂偶联的抗义寡核苷酸，抗IL-6中和抗体或kynurenine 氨基转移酶抑制剂与免疫疗法结合抑制BC免疫耐药性和转移（目标3）。 LNCRNA的致癌参与及其在中介中的作用的新兴证据免疫抑制，需要进一步表征特异性的lncrnas和未来的应用取决于他们的活动。我们的目标是证明BC免疫抵抗力的潜在机制 lncRNA和代谢物的观点。因此，一种结合了免疫检查点抑制剂和lncRNA-的策略基于的治疗策略有可能显着提高BC治疗。从长远来看，这些研究发现将通过引入针对TASC的强大临床作用来使癌症社区受益和表达TASC的LNCRNA作为有希望的治疗靶标。