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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（由申请人提供）：过继细胞移植（ACT）疗法未能实现其治疗承诺，因为使用了无效的细胞群-寿命短，耗尽和终末分化-转移到患者体内。缺乏开发长寿命T细胞效力的手段阻碍了ACT的发展。理解和操纵维持T细胞记忆的机制途径将潜在地开启对肿瘤的持久反应。与Th1细胞相比，产生il -17的CD4+ T细胞亚群Th17最近显示出对肿瘤的长期记忆。我们首先报道了Th17细胞的强大功能关键需要诱导共刺激因子（ICOS），这一发现很重要，因为我们发现了经典的共刺激分子CD28，可以破坏抗肿瘤Th17的产生。我们的研究现在表明，与CD28相比，体外用ICOS刺激Th17细胞，使它们在转移到淋巴细胞减少的小鼠体内时，具有杀死已建立的B16F10黑色素瘤的优越能力。重要的是，icos刺激的Th17的抗肿瘤效力似乎与信号赋予Th17持久记忆特性有关；icos刺激的细胞在体内长期存在，并对B16F10的再挑战产生快速的召回反应。此外，cd28刺激的Th17细胞虽然功能较差，但可以在某些药物试剂（如胰岛素、TWS119）刺激后恢复功能；重要的是，这些药物可能通过激活ICOS信号下游的细胞通路来起作用。作为加强治疗的另一种途径——并进一步证明了ICOS的重要性——我们发现，在不需要宿主预处理的情况下，给小鼠施用ICOS（而不是CD28）激动剂抗体进一步增强了Th17的治疗效果。我们建议深入了解Th17长期肿瘤免疫和持久记忆的产生，假设ICOS共刺激对于产生对肿瘤具有长期记忆反应的Th17细胞至关重要；靶向ICOS通路的组分可能导致肿瘤免疫治疗的持久疗效。Aim 1将通过研究ICOS诱导的增强Braf/Pten转移性黑色素瘤小鼠长期细胞持久性的途径，确定ICOS共刺激维持Th17细胞长期记忆和抗肿瘤活性的机制。目的2将描述药物试剂触发ICOS通路以拯救功能失调的人类Th17细胞的机制。胰岛素、Wnt- - catenin对PI3K/Akt激活的研究将揭示ICOS信号的下游事件如何逆转体外和体内受CD28刺激的人Th17细胞的受损功能。目的3将确定体内ICOS激动剂治疗增强Th17抗肿瘤活性而不需要宿主淋巴细胞消耗的机制，揭示ICOS激动剂对转移的Th17、宿主CTL和Treg细胞、功能和记忆形成的影响。总的来说，拟议的研究有望证明，操纵Th17 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。