Costimulatory mechanisms of antitumor Th17 cell immunity

抗肿瘤Th17细胞免疫的共刺激机制

• 批准号: 8596277
• 负责人: Chrystal Mary Paulos
• 金额: $ 31.02万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8596277
• 关键词: Address; Adoptive Cell Transfers; Adoptive Immunotherapy; Advanced Malignant Neoplasm; Agonist; Antibodies; CD28 Antigens; CD28 gene; CD4 Positive T Lymphocytes; CD8B1 gene; Cancer Patient; Cell physiology; Cells; Clinical; Clinical Trials; Data; Event; Figs - dietary; Generations; Goals; Human; Human Activities; Immune response; Immunity; Immunologic Memory; Immunotherapy; In Vitro; Insulin; Interferons; Interleukin-17; Interleukin-2; Lead; Life; Light; Lymphocyte; Malignant Neoplasms; Mediating; Memory; Metabolism; Metastatic Melanoma; Mitochondria; Modeling; Mus; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phenotype; Phosphotransferases; Population; Property; Proteins; Publishing; Reagent; Recurrence; Regulatory T-Lymphocyte; Reporting; Research; Role; Route; Side; Signal Transduction; T cell response; T memory cell; T-Cell Activation; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Th1 Cells; Therapeutic; Transferase; Treatment outcome; Tumor Immunity; Work; cancer immunotherapy; cancer therapy; design; effective therapy; exhaust; improved; in vivo; insight; killings; long term memory; melanoma; next generation; pre-clinical; preclinical study; preconditioning; public health relevance; response; self-renewal; therapeutic effectiveness; therapy development; trait; tumor

DESCRIPTION (provided by applicant): Adoptive cell transfer (ACT) therapies have failed to fulfill their therapeutic promise due, having employed ineffective cell populations - short-lived, exhausted, and terminally differentiated - for transfer into patients. A lack of means for developing long-lived T cell potency has hampered ACT advancement. Understanding and manipulating the mechanistic pathways that sustain T cell memory will potentially unlock durable responses to tumors. The IL-17-producing CD4+ T cell subset, Th17, has recently demonstrated long-term memory to tumors compared to Th1 cells. We first reported that robust function of Th17 cells critically requires the inducible costimulator (ICOS), a finding important considering we found the classic costimulatory molecule, CD28, to impair antitumor Th17 generation. Our studies now reveal that, in contrast to CD28, stimulating Th17 cells in vitro with ICOS endows them with a superior ability to kill established B16F10 melanoma when transferred into lymphodepleted mice. Importantly, the antitumor potency of ICOS-stimulated Th17 appears to be associated with the signal's endowing Th17 with durable memory properties; ICOS-stimulated cells persist long-term in vivo and mount rapid recall responses against B16F10 re-challenge. Further, CD28-stimulated Th17 cells, while poorly functional, could regain functionality following stimulation with certain pharmaceutical reagents (e.g., insulin, TWS119); importantly, these drugs may operate by activating cellular pathways downstream of the ICOS signal. As another route to bolstering treatment - and further demonstrating the importance of ICOS - we found that administration of an ICOS (but not CD28) agonist antibody to mice further augmented Th17 treatment outcome without the need for host preconditioning. We propose to gain insight into Th17 long-term tumor immunity and durable memory generation, hypothesizing that ICOS co-stimulation is critical for generating Th17 cells with long-lived memory responses to tumor; targeting components of the ICOS pathway may lead to durable efficacy of tumor immunotherapy. Aim 1 will identify mechanisms by which ICOS co-stimulation maintains long-term memory and antitumor activity of Th17 cells, by studying the ICOS-induced pathways that bolster long-term cell persistence in the Braf/Pten mice with metastatic melanoma. Aim 2 will characterize the mechanism(s) by which pharmaceutical reagents trigger ICOS pathways to rescue dysfunctional human Th17 cells. Studies on the activation of PI3K/Akt by insulin, Wnt-¿- catenin by TWS119 will reveal how events downstream of ICOS signaling may reverse impaired function in in vitro and in vivo human Th17 cells stimulated with CD28. Aim 3 will determine the mechanisms by which in vivo ICOS agonist therapy augments the antitumor activity of Th17 without the need for host lymphodepletion, shedding light on ICOS agonist impact on transferred Th17, and host CTL an Treg cells, function and memory formation. Overall, the proposed research is expected to demonstrate that manipulation of the Th17 ICOS pathway may sufficiently induce durable protection against the recurrence of advanced malignancies.

描述（由申请人提供）：连续性细胞转移（ACT）疗法未能实现其治疗承诺，因为采用了无效的细胞群-短寿命，耗尽和终末分化-用于转移到患者体内。缺乏开发长寿T细胞潜能的手段阻碍了ACT的发展。理解和操纵维持T细胞记忆的机制途径将有可能解锁对肿瘤的持久反应。与Th 1细胞相比，产生IL-17的CD 4 + T细胞亚群Th 17最近表现出对肿瘤的长期记忆。我们首先报道了Th 17细胞的强大功能关键需要诱导型共刺激分子（ICOS），这是一个重要的发现，因为我们发现了经典的共刺激分子CD 28，以削弱抗肿瘤Th 17的产生。我们的研究现在揭示，与CD 28相反，在体外用ICOS刺激Th 17细胞赋予它们在转移到淋巴细胞耗竭小鼠中时杀死已建立的B16 F10黑色素瘤的上级能力。重要的是，ICOS刺激的Th 17的抗肿瘤效力似乎与信号赋予Th 17持久的记忆特性有关; ICOS刺激的细胞在体内长期存在，并对B16 F10再激发产生快速回忆反应。此外，CD 28刺激的Th 17细胞虽然功能差，但在用某些药物试剂（例如，胰岛素，TWS 119）;重要的是，这些药物可以通过激活ICOS信号下游的细胞通路来发挥作用。作为支持治疗的另一种途径-并进一步证明ICOS的重要性-我们发现，向小鼠施用ICOS（而不是CD 28）激动剂抗体进一步增强了Th 17治疗结果，而不需要宿主预处理。我们建议深入了解Th 17长期肿瘤免疫和持久记忆产生，假设ICOS共刺激对于产生具有对肿瘤的长期记忆反应的Th 17细胞至关重要;靶向ICOS途径的组分可能导致肿瘤免疫治疗的持久疗效。目的1将确定ICOS共刺激维持Th 17细胞的长期记忆和抗肿瘤活性的机制，通过研究ICOS诱导的途径，支持转移性黑色素瘤Braf/Pten小鼠的长期细胞持久性。目的2将表征药物试剂触发ICOS途径以拯救功能失调的人Th 17细胞的机制。对胰岛素激活PI 3 K/Akt、TWS 119激活Wnt-β-连环蛋白的研究将揭示ICOS信号下游的事件如何逆转用CD 28刺激的体外和体内人Th 17细胞中受损的功能。目的3将确定体内ICOS激动剂治疗增强Th 17的抗肿瘤活性而不需要宿主淋巴细胞耗竭的机制，阐明ICOS激动剂对转移的Th 17和宿主CTL和Treg细胞、功能和记忆形成的影响。总的来说，拟议的研究预计将证明，操纵Th 17 ICOS通路可能足以诱导持久的保护，防止晚期恶性肿瘤的复发。