Enhancing CD8 T Cell Function by Abrogating Inhibition by Regulatory Proteins

通过消除调节蛋白的抑制来增强 CD8 T 细胞功能

• 批准号: 7014692
• 负责人: Joseph N Blattman
• 金额: $ 13.22万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7014692
• 关键词: proteins

DESCRIPTION (provided by applicant): Adoptive immunotherapy with large numbers of in vitro expanded antigen-specific CDS T cells has the potential to become a novel and safe treatment modality for cancer or viral infections, but efficacy is often limited. One obstacle is insufficient in vivo survival and retention of function by donor T cells, which can often be sustained by cotransfer of CD4 helper T cells or by IL-2 administration to substitute for CD4 help. However, specific helper CD4 T cells have not been identified for many tumors, CD4 T cells are often limiting and can be pose additional problems during treatment of HIV infection, and prolonged high-dose IL-2 supplementation can be both inefficient and toxic. Another major obstacle to adoptive immunotherapy can be the failure of transferred T cells to be effectively activated by viral and tumor targets in vivo. T cells specific for tumors often have low affinity TCRs, malignant or infected targets can have impaired antigen processing machinery or accessory signals, and prolonged recognition of target cells can induce T cell tolerance. Thus, increasing the capacity of CDS T cells for IL-2 production and autocrine IL-2 mediated proliferation, reducing the threshold for CDS T cell activation, or preventing induction of tolerance in antigen-specific CDS T cells should significantly enhance the efficacy of adoptive immunotherapeutic strategies. One potential means to increase CDS T cell avidity and function or sustain autocrine IL-2 proliferation and survival is to reduce inhibitory signals in transferred CDS T cells mediated by intracellular regulatory proteins. We have identified Cbl-b, SHP-1, and SOCS-1 as potential targets to enhance CDS T cell aviditiy and function. CDS T cells from mice deficient in these genes results in increased T cell reactivity and costimulation independent IL-2 production. The major goals of this project are to determine if decreasing the negative regulation of activation signals in CDS T cells by Cbl-b, SHP-1, or SOCS-1 by expression of dominant negative versions of these proteins, or by reducing endogenous levels of these proteins via expression of specific siRNA, can improve T cell avidity and function and render these cells more effective in therapy of chronic viral infections or malignancy in mouse models. Additionally, we will determine if abrogating inhibition by these regulatory proteins can enhance the avidity, proliferation and survival of human CDS T cells in preclinical studies. Chronic viral infections and cancer represent major public health concerns. Adoptive immunotherapy with T cells has the potential to become an effective and broadly applicable approach for the treatment of viral infections and malignancy. However, the efficacy of transferred T cells is limited by insufficient in vivo survival and function. These studies will determine if genetically modifying T cells to improve function and survival can enhance adoptive immunotherapy approaches in mouse models of chronic viral infection or malignancy as well as the survival and function of human virus and tumor specific T cells in preclinical studies.

描述（由申请人提供）：使用大量体外扩增的抗原特异性 CDS T 细胞的过继免疫疗法有潜力成为癌症或病毒感染的新型且安全的治疗方式，但疗效通常有限。其中一个障碍是供体 T 细胞的体内存活和功能保留不足，这通常可以通过 CD4 辅助 T 细胞的共转移或通过施用 IL-2 来替代 CD4 帮助来维持。然而，许多肿瘤的特异性辅助 CD4 T 细胞尚未确定，CD4 T 细胞通常具有局限性，并且可能在治疗 HIV 感染期间造成其他问题，并且长期补充高剂量 IL-2 可能既低效又有毒。过继免疫疗法的另一个主要障碍可能是转移的 T 细胞无法被体内病毒和肿瘤靶标有效激活。肿瘤特异性 T 细胞通常具有低亲和力 TCR，恶性或受感染的靶标可能具有受损的抗原处理机制或辅助信号，并且对靶细胞的长时间识别可以诱导 T 细胞耐受。因此，增加 CDS T 细胞产生 IL-2 和自分泌 IL-2 介导的增殖的能力，降低 CDS T 细胞激活的阈值，或防止诱导抗原特异性 CDS T 细胞耐受，应显着增强过继免疫治疗策略的功效。增加 CDS T 细胞亲和力和功能或维持自分泌 IL-2 增殖和存活的一种潜在方法是减少转移的 CDS T 细胞中由细胞内调节蛋白介导的抑制信号。我们已确定 Cbl-b、SHP-1 和 SOCS-1 作为增强 CDS T 细胞亲合力和功能的潜在靶标。来自缺乏这些基因的小鼠的 CDS T 细胞会导致 T 细胞反应性增加和不依赖于共刺激的 IL-2 产生。该项目的主要目标是确定通过表达 Cbl-b、SHP-1 或 SOCS-1 这些蛋白质的显性失活版本，或通过表达特定 siRNA 降低这些蛋白质的内源水平，减少 CDS T 细胞中激活信号的负调节是否可以提高 T 细胞亲和力和功能，并使这些细胞在小鼠模型中更有效地治疗慢性病毒感染或恶性肿瘤。此外，我们将在临床前研究中确定消除这些调节蛋白的抑制是否可以增强人类 CDS T 细胞的亲和力、增殖和存活率。 慢性病毒感染和癌症是主要的公共卫生问题。 T 细胞过继免疫疗法有可能成为治疗病毒感染和恶性肿瘤的有效且广泛适用的方法。然而，转移的 T 细胞的功效因体内存活和功能不足而受到限制。这些研究将确定通过基因修饰 T 细胞来改善功能和生存是否可以增强慢性病毒感染或恶性肿瘤小鼠模型的过继免疫治疗方法，以及临床前研究中人类病毒和肿瘤特异性 T 细胞的生存和功能。