Investigating the Ability of Human Blood Neutrophils to Kill Cancer

研究人类血液中性粒细胞杀死癌症的能力

• 批准号: 10648774
• 负责人: Jonathan S Reichner
• 金额: $ 8.2万
• 依托单位: RHODE ISLAND HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-05 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10648774
• 关键词: 3-Dimensional; Adherent Culture; Adhesions; Adjuvant; Adjuvant Chemotherapy; Agonist; Antibodies; Antibody Therapy; Antitumor Response; Apoptosis; Biomimetics; Breast Cancer Cell; Breast Cancer Patient; Budgets; CD18 Antigens; Cell membrane; Cell surface; Cells; Cellular Spheroids; Cessation of life; Clinic; Clinical; Collaborations; Complement; Cytotoxic T-Lymphocytes; Data; Disease; Effectiveness; Effector Cell; Elasticity; Epidermal Growth Factor Receptor; Exhibits; Extracellular Matrix; Family; Fibroblasts; Fibroins; Gel; Genetic; Greek; Host Defense; Human; ITGAM gene; ITGB2 gene; Immune; Immune response; Immunotherapy; Infection; Integrins; Invaded; Laboratories; Learning; Lectin; MDA MB 231; Macrophage; Macrophage-1 Antigen; Malignant Neoplasms; Mediating; Medical; Modeling; Natural Killer Cells; Necrosis; Neutrophil Infiltration; Organ; Organ failure; Phagocytosis; Physiological; Protocols documentation; Psychological reinforcement; Publishing; Puncture procedure; Regulatory Element; Sepsis; Silk; Site; Structure; Synapses; System; Testing; Therapeutic; Tissues; Tumor Antibodies; Work; anti-cancer; antibody-dependent cell cytotoxicity; cancer cell; cancer immunotherapy; cell killing; clinically relevant; cytotoxic; druggable target; efficacy evaluation; experimental study; insight; interest; live cell imaging; malignant breast neoplasm; migration; neoplastic cell; neutrophil; physical property; receptor; three dimensional cell culture; triple-negative invasive breast carcinoma; tumor; tumor progression

Abstract Neutrophils are not often considered as cancer killing immune cells in the same way that natural killer cells, cytotoxic T cells and macrophages. However, the inherent capability of neutrophils to be cytotoxic is clinically evident in diseases of hyperinflammation (such as sepsis) where activated neutrophils contribute to organ failure by destroying otherwise healthy cells and tissues. Therefore, neutrophils possess all the cytolytic machinery needed to be destructive to host tissues and we propose that includes cancer. What is lacking is a clearly defined targeting mechanism that can focus the cytotoxic potential of neutrophils towards cancer cells in a specific and controlled manner. This proposal will present published and preliminary evidence that neutrophils can indeed be successfully targeted to cancer cells leading to a newly described non-apoptotic cancer killing mechanism called trogoptosis. Trogoptosis (Greek: trogo; “gnaw”) is a newly described effector mechanism that brings neutrophils into the discussion of tumor killing immune cells. Trogoptosis is a form of antibody-dependent cellular cytotoxicity (ADCC) that triggers neutrophils to destroy antibody-opsonized tumor targets by forming a transient receptor-mediated synapse between the neutrophil and the tumor target. Killing occurs as a result of the neutrophil gnawing at the tumor plasma membrane and dismembering it into chunks, and is distinct from apoptosis and necrosis. Neutrophils internalize these pieces of tumor cells by phagocytosis and migrate away. Trogoptosis is dependent on the neutrophil beta2 integrin Complement Receptor 3 (CR3; CD11b/CD18; Mac-1). Antibody blockade of CR3, or neutrophils from families with genetic absence of CR3, obviate trogoptosis. Given the relative recency of this discovery, there remains much to be learned about this effector mechanism. A highly selected experimental plan is offered to fit within the budget and timeframe of an R03 yet allow rigorous testing of the hypothesis that neutrophil trogoptosis is a function that can be enhanced by agonists of neutrophil CR3 and augment the efficacy of anti-cancer antibody therapy. This R03 would develop a nascent collaboration between two laboratories with a track record in the use of biomimetic experimental systems to study breast cancer invasion and the function of human neutrophils. The experimental approach will use fibrous gels of varying stiffnesses and ECM composition that reflect differences that exist among various bodily tissues and organs. MDA-231 TNBC will be modeled as single invasive cells (Specific Aim 1) and as 3D spheroids (Specific Aim 2) in testing the trogoptoptic killing by human neutrophils introduced as tumoricidal effector cells. Additional work will determine if neutrophil CR3 is a druggable target that can enhance the effectiveness of neutrophil-dependent tumor killing and thereby potentially serve as an adjuvant to anti-tumor antibody therapy in the clinic. Our overall objective is to demonstrate that human neutrophils can be stimulated to function effectively and specifically as tumoricidal immune cells.

摘要 中性粒细胞通常不被认为是癌症杀死免疫细胞的方式与自然杀伤细胞相同， 细胞毒性T细胞和巨噬细胞。然而，临床上中性粒细胞具有细胞毒性的固有能力 在炎症过度性疾病（如脓毒症）中明显，其中活化的中性粒细胞导致器官衰竭 破坏健康的细胞和组织因此，中性粒细胞具有所有的细胞溶解机制 需要对宿主组织具有破坏性，我们认为这包括癌症。缺乏的是一个明确的定义。 靶向机制，可以集中对癌细胞的嗜中性粒细胞的细胞毒性潜力，在一个特定的， 控制的方式。这项提案将提出已发表的初步证据，表明中性粒细胞确实可以 成功靶向癌细胞，导致新描述的非凋亡癌症杀伤机制 叫做鼓膜下垂。Trogoptosis（希腊语：trogo;“gnaw”）是一种新描述的效应机制， 中性粒细胞进入肿瘤杀伤免疫细胞的讨论。牙周炎是一种抗体依赖性细胞 细胞毒性（ADCC），通过形成瞬时的细胞毒作用，触发中性粒细胞破坏抗体调理的肿瘤靶点。 受体介导的中性粒细胞和肿瘤靶点之间的突触。杀人是因为 嗜中性粒细胞啃噬肿瘤质膜并将其肢解成块，与 凋亡和坏死。中性粒细胞通过吞噬作用内化这些肿瘤细胞碎片并迁移走。 嗜中性粒细胞β 2整联蛋白补体受体3（CR 3; CD 11b/CD 18; Mac-1）依赖于Trogoptosis。 CR 3抗体阻断，或来自CR 3遗传缺失家族的中性粒细胞，视网膜色素变性。给定 虽然这一发现相对较近，但关于这种效应机制仍有许多需要了解的地方。 一个高度选择的实验计划是提供，以适应在预算和时间范围内的R 03，但允许 中性粒细胞胞突是一种可以通过以下激动剂增强的功能的假设的严格测试： 嗜中性粒细胞CR 3和增强抗癌抗体治疗的功效。这款R 03将开发出一种新生的 两个实验室之间的合作，在使用仿生实验系统方面有着良好的记录， 研究乳腺癌的侵袭和人中性粒细胞的功能。实验方法将使用纤维 不同硬度和ECM成分的凝胶，反映了不同身体组织之间存在的差异 和器官。MDA-231 TNBC将建模为单个侵袭细胞（特定目标1）和3D球体 （具体目的2）在测试作为杀肿瘤效应细胞引入的人嗜中性粒细胞的嗜光性杀伤中。 进一步的工作将确定嗜中性粒细胞CR 3是否是一个可以增强免疫治疗有效性的药物靶点。 嗜中性粒细胞依赖性肿瘤杀伤，从而潜在地用作抗肿瘤抗体疗法的佐剂 在诊所里我们的总体目标是证明人类中性粒细胞可以被刺激发挥功能， 有效且特异地作为杀肿瘤免疫细胞。