Costimulatory mechanisms of antitumor Th17 cell immunity

抗肿瘤Th17细胞免疫的共刺激机制

• 批准号: 9042984
• 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/9042984
• 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; Health; 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; neoplasm immunotherapy; next generation; pre-clinical; preclinical study; preconditioning; 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)：采用细胞移植(ACT)疗法未能实现其治疗承诺，因为使用了无效的细胞群-短期的、耗尽的和终末分化的-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的进步。理解和操纵维持T细胞记忆的机制通路将有可能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可诱导的共刺激分子(ICOS)，考虑到我们发现了经典的共刺激分子CD28，以削弱抗肿瘤Th17的生成，这一发现是重要的。我们的研究表明，与CD28相比，在体外用ICOS刺激Th17细胞，当转移到淋巴枯竭的小鼠体内时，它们具有优越的杀死已建立的B16F10黑色素瘤的能力。重要的是，ICOS刺激的Th17的抗肿瘤效力似乎与该信号赋予Th17持久的记忆特性有关；ICOS刺激的细胞在体内长期存在，并对B16F10的再次攻击做出快速回忆反应。此外，CD28刺激的Th17细胞虽然功能不佳，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发挥作用。作为加强治疗的另一种方法，并进一步证明了ICOS的重要性，我们发现，给小鼠注射ICOS(但不是CD28)激动剂抗体进一步增强了Th17治疗的结果，而不需要宿主预适应。我们建议深入了解Th17的长期肿瘤免疫和持久记忆产生，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途径的组件可能导致肿瘤免疫治疗的持久疗效。目的1通过研究ICOS诱导的增强转移性黑色素瘤BRAF/Pten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通路拯救功能失调的人Th17细胞的机制(S)。研究胰岛素对PI3K/Akt的激活作用，以及WNT-�-catenin对TWS119激活PI3K/Akt的影响，将揭示ICOS信号的下游事件如何在体外和体内逆转CD28刺激的人Th17细胞受损的功能。目的3研究ICOS激动剂体内治疗在不消耗宿主淋巴的情况下增强Th17抗肿瘤活性的机制，揭示ICOS激动剂对转移的Th17的影响，以及宿主CTL和Treg细胞、功能和记忆的形成。总体而言，这项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。