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.

采用免疫抑制剂的收养细胞免疫疗法已显示出临床承诺。很遗憾，在大多数转移性中，治疗的任务优化，无救生生存率仍然在17-21％之间实体瘤。这是通过各种肿瘤引起的异常发生的，包括免疫抑制和免疫镜肿瘤变体的出现。肿瘤生长可以通过多个诱导免疫抑制机制。我们确定了一种新型免疫抑制机制，其中肿瘤干扰宿主对淋巴细胞分化和功能至关重要的造血缺口系统。我们的固体研究肿瘤模型表明，淋巴细胞团队，特别是在CD8+T细胞和NK细胞效应之间对放射性肿瘤细胞必不可少的。但是，肿瘤中的免疫抑制慢性感染微环境阻碍了这一现象。那是可以扭转缺口功能障碍的策略淋巴细胞并恢复CD8+T – NK串扰对于有效的肿瘤和耐用性至关重要缓解。在得分资金支持下，我们发现蛋白酶体抑制剂硼替佐米调节淋巴细胞中的Notch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能会增强CD8+T和NK细胞串扰。基于这些数据，我们假设硼替佐米通过增强抗肿瘤适应性和先天免疫来克服肿瘤诱导的免疫抑制通过调节造血缺口系统的效应子串扰。在此竞争性续签申请中，我们提出将研究扩展到一个新的水平的建议，我们可以将基本见解推向CD8+T – NK 串扰和Notch介导的淋巴细胞机制进入临床前治疗。我们将测试我们的通过解决硼替佐米如何促进CD8+T – NK串扰（AIM 1）和Notch-的假设。影响抗肿瘤淋巴细胞串扰的依赖机制（AIM 2）。调查将包括通用基于使用独特的细胞类型特异性配体有条件敲除小鼠的方法生成以清楚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AIM 3中，我们建议评估硼替佐米介导的增强的治疗影响 Notch信号传导和CD8+T-NK串扰在肿瘤排斥和无救生存活中。我们将使用诱导的携带EGFR突变的肺癌模型。我们将整合硼替佐米和自适应CD8+T和NK细胞转移与EGFR靶向疗法一起评估该组合方案对肿瘤的影响缓解和无救生生存。总共，在此SC1更新应用中提出的研究将解散淋巴细胞抗肿瘤串扰的新型机制，并将提供创新的见解使用硼替佐米对Notch调节淋巴细胞机制的调节，以转化为临床相关晚期，突变或抗性肺癌的治疗。此外，它将增强癌症免疫疗法培训计划和PI过渡到非评分校外资金支持的能力。