Targeting Stat3 to Improve Immunotherapy

针对 Stat3 改善免疫​​治疗

• 批准号: 8458905
• 负责人: Hua E Yu
• 金额: $ 31.41万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8458905
• 关键词: Ablation; Agonist; Antigen Targeting; Antigen-Presenting Cells; Antigens; Antitumor Response; B-Lymphocytes; Biological Markers; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Survival; Cells; Clinical; Confocal Microscopy; Data; Dendritic Cells; Engineering; Environment; FDA approved; Future; Gene Silencing; Genes; Genetic; Homing; Image; Immune; Immune Targeting; Immune response; Immunity; Immunologics; Immunosuppression; Immunosuppressive Agents; Immunotherapy; Infiltration; Knockout Mice; Lead; Lentivirus Vector; Life; Mediating; Mediator of activation protein; Molecular; Mus; Myelogenous; Myeloid Cells; Myeloproliferative disease; Oncogenic; Pharmaceutical Preparations; Proliferating; Reagent; Regulatory T-Lymphocyte; Role; Signal Transduction; Small Interfering RNA; Specificity; Stromal Neoplasm; Suppressor-Effector T-Lymphocytes; T cell therapy; T-Cell Activation; T-Lymphocyte; Technology; Testing; Toll-like receptors; Translations; Tumor Antigens; Tyrosine Kinase Inhibitor; abstracting; cancer cell; cancer immunotherapy; cancer therapy; cell type; design; granzyme B; immune activation; improved; in vivo; inhibitor/antagonist; interleukin-23; lymph nodes; macrophage; mouse model; multi-photon; neoplastic cell; novel; perforin; receptor; research study; small molecule; transcription factor; tumor; tumor growth; tumor microenvironment

Abstract The tumor microenvironment severely limits the efficacy of various immunotherapies. For adoptive T cell therapy, the need to select/engineer and expand T cells with targeted antigen specificity while still preserving their effector function and homing capacities poses additional challenges. We and others have demonstrated that Stat3, a key oncogenic transcription factor constitutively activated in diverse cancer cells and important for tumor cell survival, is also activated in tumor stromal immune cells and potently immunosuppressive. Our preliminary studies show that targeted Stat3 gene ablation in myeloid cells results in tumor DC activation, tumor Treg cell reduction and heavy infiltration of CD8+ T cells in tumors, leading to effective antitumor immune responses. Furthermore, in mice with a Stat3-/- myeloid compartment, adoptively transferred CD8+ T cells proliferate well and are highly activated in the tumor draining lymph nodes. We were also able to capture live images by multi-photon confocal microscopy of transferred Stat3-/- CD8+ T cells efficiently infiltrating tumors, where they proliferate, leading to activation of tumor antigen-specific immune responses. We have begun to understand the cellular and molecular mechanisms that allow Stat3 in both tumor myeloid cells and T cells to impede T-cell mediated antitumor immunity. In this application, we propose to further define these cellular and molecular mechanisms and thereby identifying additional targets to optimize Stat3 targeting and T cell therapy. To facilitate potential future clinical translation, we will also test two reagents, both of which have shown positive effects on the tumor immunologic environment, for their potential to improve T cell therapies. One is a novel Toll-like receptor (TLR) agonist-siRNA conjugate, a technology platform we have recently developed, and is capable of immune activation and targeted gene silencing of desired immunologic checkpoints such as Stat3 in myeloid and B cells. The other is an FDA-approved tyrosine kinase inhibitor, sunitinib, as our preliminary data suggested it inhibited Stat3 in tumor cells, tumor-infiltrating dendritic cells and myeloid-derived suppressor cells. Additionally, we will test antitumor efficacy by silencing Stat3 in T cells ex vivo with lentiviral-siRNAs. The proposed studies may lead to new strategies to expand and activate transferred T cells in vivo, thereby overcoming several major hurdles facing T cell therapy, and significantly improve its efficacy for cancer treatment.

抽象的 肿瘤微环境严重限制了各种免疫疗法的功效。 对于过继性 T 细胞疗法，需要选择/设计和扩增具有靶向性的 T 细胞 抗原特异性，同时仍保留其效应子功能和归巢能力 带来了额外的挑战。我们和其他人已经证明了 Stat3，一个关键的 在多种癌细胞中组成型激活的致癌转录因子和 对肿瘤细胞的存活很重要，也在肿瘤基质免疫细胞中被激活， 强效免疫抑制作用。我们的初步研究表明，靶向 Stat3 基因 骨髓细胞的消融导致肿瘤 DC 激活、肿瘤 Treg 细胞减少和 CD8+ T细胞在肿瘤中大量浸润，导致有效的抗肿瘤免疫 回应。此外，在具有 Stat3-/- 骨髓区室的小鼠中，过继地 转移的 CD8+ T 细胞增殖良好，并在肿瘤引流中高度激活 淋巴结。我们还能够通过多光子共焦捕获实时图像 转移的 Stat3-/- CD8+ T 细胞有效浸润肿瘤的显微镜检查 增殖，导致肿瘤抗原特异性免疫反应的激活。我们有 开始了解 Stat3 的细胞和分子机制 肿瘤骨髓细胞和 T 细胞阻碍 T 细胞介导的抗肿瘤免疫。在这个 应用，我们建议进一步定义这些细胞和分子机制 从而确定其他靶点来优化 Stat3 靶向和 T 细胞治疗。到 为了促进未来潜在的临床转化，我们还将测试两种试剂，这两种试剂 已显示出对肿瘤免疫环境的积极影响，因为它们具有潜在的 改善 T 细胞疗法。一种是新型Toll样受体（TLR）激动剂-siRNA 结合物，我们最近开发的一个技术平台，能够免疫 所需免疫检查点（例如 Stat3）的激活和靶向基因沉默 存在于骨髓细胞和 B 细胞中。另一种是FDA批准的酪氨酸激酶抑制剂舒尼替尼， 正如我们的初步数据表明它抑制肿瘤细胞中的 Stat3、肿瘤浸润 树突状细胞和骨髓源性抑制细胞。此外，我们将测试抗肿瘤作用 通过使用慢病毒-siRNA 体外沉默 T 细胞中的 Stat3 来发挥功效。拟议的研究 可能会导致在体内扩增和激活转移的 T 细胞的新策略，从而 克服了T细胞治疗面临的几个主要障碍，并显着提高了其治疗效果 对癌症治疗的功效。