Immunomodulatory effects of bortezomib on antitumor CD8 T-NK cell crosstalk

硼替佐米对抗肿瘤 CD8 T-NK 细胞串扰的免疫调节作用

• 批准号: 9770536
• 负责人: Anil Shanker
• 金额: $ 32.74万
• 依托单位: MEHARRY MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-12 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9770536
• 关键词: Address; Adoptive Cell Transfers; Adoptive Immunotherapy; Adoptive Transfer; Affect; Alpha Cell; Antigens; Apoptosis; Avidity; Bortezomib; CD8-Positive T-Lymphocytes; CD8B1 gene; Cancer Model; Cell Therapy; Chronic; Clinic; Clinical; Cytolysis; Data; Dendritic Cells; Development; Disease remission; Dose; Effector Cell; Epidermal Growth Factor Receptor; Epitopes; Exhibits; Extramural Activities; Functional disorder; Funding; Goals; Hemagglutinin; Hematopoietic; Image; Immune; Immune checkpoint inhibitor; Immune response; Immunosuppression; Immunosuppressive Agents; Inflammation; Inflammatory; Interleukin 2 Receptor; Investigation; Knockout Mice; Ligands; Lung Adenocarcinoma; Lymphocyte; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Modeling; Molecular; Mus; Mutation; Natural Killer Cells; Phosphorylation; Proteasome Inhibitor; Refractory; Regimen; Relapse; Resistance; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Solid Neoplasm; Survival Rate; System; T-Cell Receptor; T-Lymphocyte and Natural Killer Cell; Testing; Therapeutic; Tissues; Training Programs; Translations; Tumor Debulking; Tumor Escape; Tumor Immunity; Variant; base; cancer cell; cancer immunotherapy; cell type; clinically relevant; combinatorial; genetic approach; immunoregulation; improved functioning; innovation; insight; intravital imaging; lymph nodes; lymphocyte proliferation; melanoma; mutant; neoplastic cell; notch protein; novel; novel strategies; p65; pre-clinical; preclinical study; prevent; response; targeted treatment; treatment optimization; tumor; tumor eradication; tumor growth; tumor microenvironment

Adoptive cell immunotherapy with immune checkpoint inhibitors has shown clinical promise. Unfortunately, despite optimizations of treatments, relapse-free survival rates still range between 17-21% in most metastatic solid tumors. This occurs via various tumor-induced abnormalities including immunosuppression and emergence of immune escape tumor variants. Tumor growth can induce immunosuppression by multiple mechanisms. We identified a novel mechanism of immunosuppression wherein tumor interferes with the host hematopoietic Notch system that is critical for lymphocyte differentiation and function. Our studies in solid tumor models demonstrate that lymphocyte teamwork, specifically between CD8+T cell and NK cell effectors, is essential to eradicate tumor cells. However, immunosuppressive chronic inflammation in the tumor microenvironment hinders this phenomenon. Thus, strategies that can reverse Notch dysfunction in lymphocytes and restore the CD8+T–NK crosstalk are critical for effective tumor eradication and durable remission. Facilitated by SCORE funding support, we found that proteasome inhibitor bortezomib modulates Notch signaling in lymphocytes and enhances their antitumor activity. Additionally, our data also indicate that bortezomib may augment CD8+T and NK cell crosstalk. Based on these data, we hypothesize that bortezomib overcomes tumor-induced immunosuppression by enhancing the antitumor adaptive and innate immune effector crosstalk via modulation of the hematopoietic Notch system. In this competing renewal application, we propose to extend our studies to the next level whereby we can advance our basic insights into CD8+T–NK crosstalk and Notch-mediated lymphocyte mechanisms into a preclinical therapeutic setting. We will test our hypothesis by addressing how bortezomib can facilitate the CD8+T–NK crosstalk (Aim 1), and Notch- dependent mechanisms affecting antitumor lymphocyte cross-talk (Aim 2). Investigations will include genetic approaches based on the use of unique cell type-specific Notch ligand conditional knockout mice that we have generated to clearly define the roles of dendritic cell-bound ligands in antitumor CD8+T–NK functional crosstalk. In Aim 3, we propose to evaluate the therapeutic impact of bortezomib-mediated enhancement of Notch signaling and CD8+T–NK crosstalk on tumor rejection and relapse-free survival. We will use an inducible lung cancer model carrying EGFR mutations. We will integrate bortezomib and adoptive CD8+T and NK cell transfers along with EGFR-targeted therapy and evaluate the impact of this combinatorial regimen on tumor remission and relapse-free survival. Altogether, the studies proposed in this SC1 renewal application will unravel novel mechanisms underlying lymphocyte antitumor crosstalk, and will provide innovative insight into modulation of Notch regulatory lymphocyte mechanisms using bortezomib for translation into clinically relevant therapeutics in advanced-stage, mutant, or resistant lung cancer. In addition, it would enhance the cancer immunotherapy training program and PI’s capacity to transition to non-SCORE extramural funding support.

使用免疫检查点抑制剂的过继细胞免疫治疗已显示出临床应用前景。不幸的是， 尽管优化了治疗方法，但大多数转移性肿瘤的无复发存活率仍在17%-21%之间。 实体瘤。这是通过各种肿瘤诱导的异常发生的，包括免疫抑制和 出现免疫逃逸肿瘤变异体。肿瘤生长可通过多种途径诱导免疫抑制 机制。我们发现了一种新的免疫抑制机制，即肿瘤干扰宿主。 对淋巴细胞分化和功能至关重要的造血Notch系统。我们扎扎实实的学习 肿瘤模型表明，淋巴细胞之间，特别是CD8+T细胞和NK细胞效应器之间的协同作用 对根除肿瘤细胞至关重要。然而，免疫抑制的慢性炎症在肿瘤中 微环境阻碍了这一现象。因此，可以逆转Notch功能障碍的策略 淋巴细胞和恢复CD8+T-NK串扰是有效根除和持久治疗肿瘤的关键 减刑。在SCORE基金的支持下，我们发现蛋白酶体抑制剂Bortezomib调节 阻断淋巴细胞内的信号转导，增强其抗肿瘤活性。此外，我们的数据还表明， Bortezomib可增强CD8+T细胞和NK细胞的串扰。根据这些数据，我们假设波特佐米 通过增强抗肿瘤获得性免疫和先天免疫克服肿瘤免疫抑制 通过调节造血学Notch系统产生的效应器串扰。在这项竞争性续订申请中，我们 建议将我们的研究扩展到下一个水平，从而促进我们对CD8+T-NK的基本认识 串扰和Notch介导的淋巴细胞机制进入临床前治疗环境。我们将测试我们的 通过解决Bortezomib如何促进CD8+T-NK串扰(目标1)和Notch- 影响抗肿瘤淋巴细胞串扰的依赖机制(目标2)。调查将包括基因 基于我们拥有的独特的细胞类型特异性Notch配体条件性基因敲除小鼠的方法 明确定义树突状细胞结合配体在抗肿瘤CD8+T-NK功能中的作用 相声。在目标3中，我们建议评估Bortezomib介导的增强 Notch信号和CD8+T-NK信号对肿瘤排斥反应和无复发生存期的影响。我们将使用诱导式 携带EGFR突变的肺癌模型。我们将整合Bortezomib和过继CD8+T细胞和NK细胞 与EGFR靶向治疗一起转移，并评估这种联合方案对肿瘤的影响 缓解和无复发生存。综上所述，在这份SC1续期申请中建议的研究将 揭开淋巴细胞抗肿瘤串扰的新机制，并将为 用硼替佐米翻译成临床相关的Notch调节淋巴细胞机制 晚期、突变或耐药肺癌的治疗。此外，它还会增强癌症 免疫治疗培训计划和PI过渡到非得分校外资金支持的能力。