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

• 批准号: 8475316
• 负责人: Anil Shanker
• 金额: $ 36.38万
• 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 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8475316
• 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

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）：癌症仍然是死亡的主要原因，对少数民族社区造成了不成比例的损失。最常见的癌症是对传统治疗的难治性。通过最近对癌症免疫监察机制的欣赏，我们的长期目标是阐明癌症消退的免疫机制，并开发可以特异性消除恶性细胞并为癌症患者提供持久益处的免疫疗法方法。在包括癌症在内的各种病理生理模型中的最新研究表明，适应性和先天免疫效应细胞中必不可少的合作性。我们在肥大细胞瘤模型中的工作表明，CD8+ T细胞为休眠天然杀手（NK）细胞提供了必要的“帮助”，从而引起其抗肿瘤功能。 T细胞和NK细胞效应子机制的这种合作性通过防止抗原缺陷型肿瘤逃生变体的发展而导致肿瘤回归。我们在拒绝小鼠肾细胞癌Renca以及其他人在控制乳腺，膀胱和腹膜内质质肿瘤中也观察到了组合CD8+ T细胞和NK细胞的相似作用。这表示NK细胞和T细胞在肿瘤排斥中的功能合作性的重要性。然而，如诱导性肿瘤模型所示，在免疫抑制性慢性炎症的条件下，T细胞和NK细胞的这种保护性团队工作失败了。因此，必须通过覆盖肿瘤诱导的免疫抑制来研究新型组合治疗策略及其机械交叉对话，以减轻肿瘤负担并增强抗肿瘤免疫效应的功能。基于我们的初步数据，我们假设将肿瘤细胞死亡敏化硼替佐米的施用与收养的NK细胞转移和免疫刺激性缺口的激活相结合，应通过调节阴性免疫调节回路来增强抗肿瘤免疫效应的功能。这种组合策略应克服慢性炎症在肿瘤微环境中的免疫抑制作用，并提高针对癌症的治疗益处。为了检验我们的假设，我们建议解决以下特定目的：目标1：表征硼替佐米对肿瘤浸润淋巴样和髓样细胞的影响，以及肿瘤微环境中的细胞因子和趋化因子的产生。目标2：评估硼替佐米对NK细胞效应子响应的影响。 AIM 3：在已建立的肿瘤中优化NK细胞产卵疗法与硼替佐米和聚集的多价DLL1治疗。该提案将是攻击肿瘤特异性T细胞和NK细胞之间抗肿瘤功能合作的不足区域的首次尝试。结果将为设计与癌症与大多数常规治疗相关的有效免疫疗法方案的设计提供新的见解，并将对癌症以外的病理生理状况产生影响。