Costimulatory mechanisms of antitumor Th17 cell immunity

抗肿瘤Th17细胞免疫的共刺激机制

基本信息

批准号：
9260847
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
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9260847
关键词：
Address Adoptive Cell Transfers Adoptive Immunotherapy Adoptive Transfer Advanced Malignant Neoplasm Adverse effects Agonist Antibodies CD28 Antigens CD28 gene CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Cancer Patient Cell physiology Cells Clinical Clinical Trials Data Development Event Generations Goals Human Human Activities Immune response Immunity Immunologic Memory Immunotherapy Impairment In Vitro Insulin Interferons Interleukin-17 Interleukin-2 Lead 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 Signal Transduction T memory cell T-Cell Activation T-Lymphocyte 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 neoplasm immunotherapy next generation pre-clinical preclinical study preconditioning public health relevance response self-renewal therapeutic effectiveness therapy development trait tumor

项目摘要

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（由适用提供）：收养细胞转移（ACT）疗法未能履行其应有的治疗诺言，使员工无效的细胞种群 - 短暂的，疲惫的且终极分化 - 用于转移到患者中。缺乏发展长期T细胞效力的方法阻碍了行动的进步。了解和操纵维持T细胞记忆的机理途径可能会解锁对肿瘤的持久反应。与Th1细胞相比，产生IL-17的CD4+ T细胞子群Th17最近证明了肿瘤的长期记忆。我们首先报道了Th17细胞的鲁棒功能严重要求诱导型共刺激器（ICOS），这是一个重要的考虑因素，我们发现了经典的共示基分子CD28，以损害抗肿瘤Th17的生成。我们的研究现在表明，与CD28相比，用ICOS刺激Th17细胞的刺激，使它们具有较高的能力，可以杀死已转移到淋巴细胞内的小鼠中时杀死已建立的B16F10黑色素瘤。重要的是，ICOS刺激的Th17的抗肿瘤效力似乎与信号赋予具有持久记忆特性的TH17相关。 ICOS刺激的细胞在体内长期持续存在，并针对B16F10重新挑战的快速回忆反应。此外，通过某些药物试剂（例如胰岛素，TWS119）刺激后，CD28刺激的Th17细胞虽然功能较差，但功能较差，但可以保持功能。重要的是，这些药物可以通过激活ICOS信号下游的细胞途径来起作用。作为弯曲治疗的另一条途径 - 进一步证明了ICOS的重要性 - 我们发现对小鼠的ICO（而不是CD28）激动剂抗体的给药进一步增强了TH17治疗结果，而无需进行宿主预处理。我们建议深入了解TH17长期肿瘤免疫史和耐用记忆的产生，假设ICOS共刺激对于产生具有长期记忆对肿瘤的记忆反应的Th17细胞至关重要。 ICOS途径的靶向成分可能会导致肿瘤免疫疗法的持久效率。 AIM 1将通过研究ICOS诱导的途径来鉴定ICOS共刺激保持Th17细胞的长期记忆和抗肿瘤活性的机制，这些途径增强了带有转移性黑色素瘤的BRAF/PTEN小鼠长期细胞持久性的途径。 AIM 2将表征药物试剂触发ICOS途径来挽救功能失调的人TH17细胞的机制。 TWS119对PI3K/Akt激活PI3K/AKT的研究将揭示ICOS信号传导下游的事件如何在体外和体内和体内用CD28刺激的人体TH17细胞逆转功能。 AIM 3将确定体内ICOS激动剂治疗的机制增加Th17的抗肿瘤活性，而无需宿主淋巴结蛋白，对ICOS激动剂对转移的Th17的影响以及宿主CTL的影响以及宿主CTL散发出来，功能和记忆形成，功能和记忆形成。总体而言，拟议的研究预计将证明对TH17 ICOS途径的操纵可能足以诱导持久的保护，以防止晚期恶性肿瘤复发。