Long Noncoding RNA Advocates Immune Resistant Microenvironment

项目摘要 从历史上看，大多数相关研究仅询问了乳腺癌细胞中的经典途径， 在开发针对三阴性乳腺癌（TNBC）的临床药物方面几乎没有成功。免疫疗法， 包括PD-1/PD-L1阻断，最近已被证明在治疗许多肿瘤谱系中有效，但 大多数TNBC病例被认为是耐药或免疫静止肿瘤，并且对化疗无反应。 单检查点治疗这些挑战要求定义潜在的分子机制， 在TNBC进展期间发生的免疫抑制。我们证明了肿瘤患者施万 细胞（称为TASC）在促进免疫抑制微环境中起重要作用。肿瘤- 常驻雪旺细胞表达一种lncRNA，其调节RAF 1介导的TDO 2磷酸化 （色氨酸2，3-双加氧酶），从而促进TDO 2的酶活性和色氨酸的催化作用。 (Trp)犬尿氨酸（Kynurenine）。在肿瘤微环境中释放的Kyn进一步促进肿瘤细胞的扩增。 MDSC（髓源性抑制细胞）和效应T细胞的静止。因此，考虑到肿瘤- 作为治疗靶点的相关雪旺细胞和lncRNA可能潜在地使TNBC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， lncRNA在乳腺癌中的作用，从而可以开发出降低TNBC发病率和死亡率的改进策略。 我们的中心假设是PVT 1促进肿瘤相关雪旺细胞中TDO 2的磷酸化， 促进三阴性乳腺癌免疫耐药性，这可以在体内使用靶向的 疗法我们将从以下几个方面来验证我们的假设。1)我们将展示 肿瘤相关的雪旺细胞依赖性免疫抑制（Aim 1）。我们将确定潜在的 PVT 1调控TDO 2酶活性的分子机制（Aim 2）。3)我们将确定 使用小分子抑制剂和小分子抑制剂研究肿瘤驻留的雪旺细胞和PVT 1的功能重要性 分子标记物缀合的Pvt 1反义寡核苷酸与免疫疗法组合（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，保证进一步表征雪旺细胞特异性lncRNA和未来的应用 取决于它们的活动。我们的目标是证明在肿瘤相关的雪旺细胞中表达的PVT 1， 可以作为一种诊断标志物，预测癌症对免疫疗法的敏感性。因此，一项战略， 结合免疫检查点阻断剂和基于lncRNA的治疗策略， 先进的TNBC治疗。从长远来看，这些研究结果将使癌症社区受益， 介绍了靶向肿瘤相关的雪旺细胞和表达雪旺细胞的强大临床效果， lncRNA作为有前途的治疗靶点。

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.