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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

基本信息

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
项目类别：
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

项目摘要

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免疫细胞免疫疗法已显示出临床前景。不幸的是，尽管优化了治疗，但在大多数转移性肿瘤中，无复发生存率仍在17-21%之间。实体瘤这是通过各种肿瘤诱导的异常发生的，包括免疫抑制和免疫逃逸肿瘤变体的出现。肿瘤生长可通过多种途径诱导免疫抑制。机制等我们发现了一种新的免疫抑制机制，其中肿瘤干扰宿主造血Notch系统是淋巴细胞分化和功能的关键。我们的研究在固体肿瘤模型表明，淋巴细胞协同作用，特别是在CD 8 +T细胞和NK细胞效应子之间，对根除肿瘤细胞至关重要。然而，肿瘤中的免疫抑制性慢性炎症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CD 8 +T-NK串扰对于有效的肿瘤根除和持久的治疗是至关重要的。缓解。在SCORE基金支持的帮助下，我们发现蛋白酶体抑制剂硼替佐米调节了 Notch在淋巴细胞中的信号传导并增强其抗肿瘤活性。此外，我们的数据还表明，硼替佐米可增加CD 8 +T和NK细胞的相互作用。基于这些数据，我们假设硼替佐米通过增强抗肿瘤适应性免疫和先天免疫来克服肿瘤诱导的免疫抑制通过调节造血Notch系统的效应子串扰。在这个竞争性的续期申请中，我们我建议将我们的研究扩展到一个新的水平，从而我们可以推进我们对CD 8 +T-NK的基本见解串扰和Notch介导的淋巴细胞机制应用于临床前治疗环境。我们将测试我们的通过解决硼替佐米如何促进CD 8 +T-NK串扰的假设（目的1），以及Notch- 影响抗肿瘤淋巴细胞串扰的依赖性机制（目的2）。调查将包括遗传基于使用独特的细胞类型特异性Notch配体条件性敲除小鼠的方法，产生了明确定义树突状细胞结合的配体在抗肿瘤CD 8 +T-NK功能中的作用，串话。在目标3中，我们建议评估硼替佐米介导的增强肿瘤细胞增殖的治疗作用。 Notch信号传导和CD 8 +T-NK串扰对肿瘤排斥和无复发生存的影响我们会用诱导剂携带EGFR突变的肺癌模型。我们将整合硼替佐米和过继性CD 8 +T和NK细胞，转移沿着EGFR靶向治疗，并评估这种组合方案对肿瘤的影响缓解和无复发生存期。总而言之，本次SC 1更新申请中提出的研究将解开淋巴细胞抗肿瘤串扰的新机制，并将提供创新的见解，使用硼替佐米调节Notch调节性淋巴细胞机制，用于翻译成临床相关的晚期、突变型或耐药型肺癌的治疗。此外，它还会增强癌症免疫治疗培训计划和PI过渡到非SCORE校外资助支持的能力。