Defining the effects of bortezomib on NK cell activation in cancer

确定硼替佐米对癌症 NK 细胞活化的影响

基本信息

批准号：
8700356
负责人：
Anil Shanker
金额：
$ 35.28万
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 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8700356
关键词：
Activated Natural Killer Cell Address Affect Antigens Area Biological Bladder Bortezomib CD8B1 gene Cancer Patient Cause of Death Cell Death Cessation of life Chronic Communities Complex Data Defect Development Dose Effector Cell Hemagglutinin Immune Immunologic Monitoring Immunosuppression Immunosuppressive Agents Immunotherapy Inflammation Lead Ligands Ligation Lymphocyte Lymphoid Cell Lymphopoiesis Malignant Neoplasms Mammary gland Mast Cell Neoplasm Mediating Mediator of activation protein Mesenchymal Cell Neoplasm Minority Modeling Molecular Target Mus Myeloid Cells NK Cell Activation Natural Killer Cells PI3K/AKT Pathway interactions Production Proteasome Inhibition Proteasome Inhibitor Proto-Oncogene Proteins c-akt Protocols documentation Publishing Refractory Renal Cell Carcinoma Role Signal Pathway Signal Transduction System T-Lymphocyte Testing Therapeutic Tumor Burden Tumor Escape Variant Velcade Work base cancer cell cancer regression caspase-8 chemokine combinatorial conventional therapy cytokine cytotoxicity design improved influenzavirus insight intraperitoneal neoplastic cell notch protein novel prevent public health relevance receptor response tumor tumor microenvironment tumor progression

项目摘要

DESCRIPTION (provided by applicant): Cancer remains the leading cause of death with a disproportionate toll on minority communities. Most common cancers are refractory to traditional treatments. With recent appreciation of cancer immunosurveillance mechanisms, our long-term objective is to elucidate immune mechanisms of cancer regression and to develop immunotherapy approaches that can specifically eliminate malignant cells and provide durable benefits in cancer patients. Recent studies in various pathophysiological models of immune rejection, including cancer, suggest an indispensable co-operativity in adaptive and innate immune effector cells. Our work in a mastocytoma model demonstrated that CD8+ T cells provided a necessary "help" to dormant natural killer (NK) cells in eliciting their antitumor function. This co-operativity of T cell and NK cell effector mechanisms led to complete tumor regression, by preventing the development of antigen-deficient tumor escape variants. A similar role of combined CD8+ T cells and NK cells was also observed by us in the rejection of mouse renal cell carcinoma Renca and by others in the control of mammary, bladder and intraperitoneal mesenchymal tumors. This signifies the importance of functional co-operativity of NK cells and T cells in tumor rejection. However, this protective team-work of T cells and NK cells fails in conditions of immunosuppressive chronic inflammation intrinsic to aggressive tumors as shown in inducible tumor models. Thus, it is imperative to investigate novel combinatorial therapeutic strategies and their mechanistic cross-talk to reduce tumor burden and potentiate anti-tumor immune effector functions by overriding tumor-induced immunosuppression. Based on our preliminary data, we hypothesize that combining tumor cell-death sensitizing bortezomib administration with adoptive NK cell transfer and immunostimulatory Notch activation should strengthen anti-tumor immune effector functions by modulating negative immune-regulatory circuits. This combinatorial strategy should overcome immunosuppressive effects of the chronic inflammation in tumor microenvironment and enhance therapeutic benefits against cancer. To test our hypothesis, we propose to address the following specific aims: Aim 1: Characterize the impact of bortezomib administration on tumor-infiltrating lymphoid and myeloid cells and their cytokine and chemokine production in the tumor microenvironment. Aim 2: Assess the effects of bortezomib on NK cell effector responses. Aim 3: Optimize NK cell adoptive therapy in combination with bortezomib and clustered multivalent DLL1 treatments in an established tumor. This proposal will be the first attempt at attacking the underexplored area of how anti-tumor functional co-operativity between the tumor- specific T cells and NK cells can be enhanced in the context of molecular targeting based on proteasome inhibition and immunostimulatory Notch signaling. The results will provide new insights for designing effective immunotherapy protocols relevant to cancers refractory to most conventional treatments and will have implications for pathophysiological conditions beyond cancer.

描述（由申请人提供）：癌症仍然是主要的死亡原因，对少数族裔社区造成的死亡人数不成比例。大多数常见的癌症对传统治疗都难以治愈。随着最近对癌症免疫监视机制的认识，我们的长期目标是阐明癌症消退的免疫机制，并开发能够特异性消除恶性细胞并为癌症患者提供持久益处的免疫治疗方法。最近对包括癌症在内的各种免疫排斥的病理生理学模型的研究表明，适应性和先天免疫效应细胞之间存在着不可或缺的协同作用。我们在肥大细胞瘤模型中的工作表明，CD8+ T 细胞为休眠的自然杀伤 (NK) 细胞激发其抗肿瘤功能提供了必要的“帮助”。 T 细胞和 NK 细胞效应机制的这种协同作用，通过防止抗原缺陷型肿瘤逃逸变体的发展，导致肿瘤完全消退。我们还在小鼠肾细胞癌 Renca 的排斥反应中观察到了 CD8+ T 细胞和 NK 细胞组合的类似作用，其他人在控制乳腺、膀胱和腹膜内间质肿瘤中也观察到了类似的作用。这表明 NK 细胞和 T 细胞的功能协同在肿瘤排斥中的重要性。然而，如诱导肿瘤模型所示，T 细胞和 NK 细胞的这种保护性团队合作在侵袭性肿瘤固有的免疫抑制性慢性炎症条件下失败。因此，有必要研究新的组合治疗策略及其机制串扰，以通过克服肿瘤诱导的免疫抑制来减轻肿瘤负荷并增强抗肿瘤免疫效应功能。根据我们的初步数据，我们假设将肿瘤细胞死亡致敏的硼替佐米给药与过继性 NK 细胞转移和免疫刺激性 Notch 激活相结合，应通过调节负性免疫调节回路来增强抗肿瘤免疫效应功能。这种组合策略应该克服肿瘤微环境中慢性炎症的免疫抑制作用，并增强对癌症的治疗效果。为了检验我们的假设，我们建议解决以下具体目标：目标 1：表征硼替佐米给药对肿瘤浸润淋巴和骨髓细胞及其在肿瘤微环境中细胞因子和趋化因子产生的影响。目标 2：评估硼替佐米对 NK 细胞效应反应的影响。目标 3：优化 NK 细胞过继疗法，结合硼替佐米和集群多价 DLL1 治疗已确定的肿瘤。该提案将是首次尝试攻克尚未开发的领域，即如何在基于蛋白酶体抑制和免疫刺激性 Notch 信号传导的分子靶向背景下增强肿瘤特异性 T 细胞和 NK 细胞之间的抗肿瘤功能协同性。这些结果将为设计与大多数传统治疗难治性癌症相关的有效免疫治疗方案提供新的见解，并将对癌症以外的病理生理学状况产生影响。